Tricyclic diazepine vasopressin antagonists and oxytocin antagonists

ABSTRACT

Tricyclic diazepines of the formula: ##STR1## wherein A, B, D, E, F, Y and Z are defined in the specification which compounds have vasopressin and oxytocin antagonist activity.

This application is a divisional application of U.S. application Ser.No. 08/254,822, filed Jun. 13, 1994, now U.S. Pat. No. 5,516,774, whichis a CIP of U.S. application Ser. No. 08/100,004, filed Jul. 29, 1993,now abandoned.

FIELD OF THE INVENTION

This invention relates to new tricyclic nonpeptide vasopressinantagonists which are useful in treating conditions where decreasedvasopressin levels are desired, such as in congestive heart failure, indisease conditions with excess renal water reabsorption and conditionswith increased vascular resistance and coronary vasoconstriction.

BACKGROUND OF THE INVENTION

Vasopressin is released from the posterior pituitary either in responseto increased plasma osmolarity detected by brain osmoreceptors ordecreased blood volume and blood pressure sensed by low-pressure volumereceptors and arterial baroreceptors. The hormone exerts its actionsthrough two well defined receptor subtypes: vascular V₁ and renalepithelial V₂ receptors. Vasopressin-induced antidiuresis, mediated byrenal epithelial V₂ receptors, helps to maintain normal plasmaosmolarity, blood volume and blood pressure.

Vasopressin is involved in some cases of congestive heart failure whereperipheral resistance is increased. V₁ antagonists may decrease systemicvascular resistance, increase cardiac output and prevent vasopressininduced coronary vasoconstriction. Thus, in conditions with vasopressininduced increases in total peripheral resistance and altered local bloodflow, V₁ -antagonists may be therapeutic agents.

The blockade of V₂ receptors may be useful in treating diseasescharacterized by excess renal reabsorption of free water. Antidiuresisis regulated by the hypothalamic release of vasopressin (antidiuretichormone) which binds to specific receptors on renal collecting tubulecells. This binding stimulates adenylyl cyclase and promotes thecAMP-mediated incorporation of water pores into the luminal surface ofthese cells. V₂ antagonists may correct the fluid retention incongestive heart failure, liver cirrhosis, nephrotic syndrome, centralnervous injuries, lung disease and hyponatremia.

Elevated vasopressin levels occur in congestive heart failure which ismore common in older patients with chronic heart failure. In patientswith hyponatremic congestive heart failure and elevated vasopressinlevels, a V₂ antagonist may be beneficial in promoting free waterexcretion by antagonizing the action of antiduretic hormone. On thebasis of the biochemical and pharmacological effects of the hormonesantagonists of vasopressin are expected to be therapeutically useful inthe treatment and/or prevention of hypertension, cardiac insufficiency,coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis,congestive heart failure, nephrotic syndrome, brain edema, cerebralischemia, cerebral hemorrhage-stroke, thrombosis-bleeding, abnormalstates of water retention.

The following prior art references describe peptide vasopressinantagonists; M. Manning et al., J. Med. Chem., 35, 382(1992); M. Manninget al., J. Med. Chem., 35, 3895(1992); H. Gavras and B. Lammek, U.S.Pat. No. 5,070,187 (1991); M. Manning and W. H. Sawyer, U.S. Pat. No.5,055,448 (1991); F. E. Ali, U.S. Pat. No. 4,766,108(1988); R. R.Ruffolo et al., Drug News and Perspective, 4(4), 217, (May)(1991). P. D.Williams et al., have reported on potent hexapeptide oxytocinantagonists [J. Med. Chem., 35 3905(1992)] which also exhibit weakvasopressin antagonist activity in binding to V₁ and V₂ receptors.Peptide vasopressin antagonists suffer from a lack or oral activity andmany of these peptides are not selective antagonists since they alsoexhibit partial agonist activity.

Non-peptide vasopressin antagonists have recently been disclosed, Y.Yamamura et al., Science, 252, 579(1991); Y. Yamamura et al., Br. J.Pharmacol., 105, 787(1992), Ogawa et al., (Otsuka Pharm Co., LTD.) EP0514667-A1; JP 04154765-A; EPO 382185-A2; and W09105549. Carbostyrilderivatives and pharmaceutical compositions containing the same aredisclosed by Ogawa et al., (Otsuka Pharm. Co.) in EP 470514A.Non-peptide oxytocin and vasopressin antagonist have been disclosed byMerck and Co.; M. G. Bock and P. D. Williams, EP 0533242A; M. G. Bock etal., EP 0533244A; J. M. Erb, D. F. Verber, P. D. Williams, EP0533240A;K. Gilbert et al., EP 0533243A.

Premature birth can cause infant health problems and mortality and a keymediator in the mechanism of labor is the peptide hormone oxytocin. Onthe basis of the pharmacological action of oxytocin, antagonists of thishormone are useful in the prevention of preterm labor, B. E. Evans etal., J. Med. Chem., 35, 3919(1992), J. Med. Chem., 36, 3993(1993) andreferences therein. The compounds of this invention are antagonists ofthe peptide hormone oxytocin and are useful in the control of prematurebirth.

The present invention relates to novel tricyclic derivatives whichexhibit antagonist activity at V₁ and/or V₂ receptors and exhibit invivo vasopressin antagonist activity. The compounds also exhibitantagonists activity of oxytocin receptors.

SUMMARY OF THE INVENTION

This invention relates to new compounds selected from those of thegeneral formula I: ##STR2## wherein Y is a moiety selected from;--(CH₂)_(n) --wherein n is an integer from 0 to 2, ##STR3## A--B is amoiety selected from ##STR4## wherein m is an integer from 1 to 2provided that when Y is --(CH₂)_(n) --and n is 2, m may also be zero andwhen n is zero, m may also be three, provided also that when Y is--(CH₂)_(n) --and n is 2, m may not be two; and the moiety: ##STR5##represents: (1) fused phenyl or fused substituted phenyl optionallysubstituted by one or two substituents selected from (C₁ -C₃) loweralkyl, halogen, amino, (C₁ -C₃) lower alkoxy or (C₁ -C₃) loweralkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ringhaving one heteroatom selected from O, N or S; (3) a 6-membered aromatic(unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or6-membered aromatic (unsaturated) heterocyclic ring having two nitrogenatoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring havingone nitrogen atom together with either one oxygen or one sulfur atom;wherein the 5 or 6-membered heterocyclic rings are optionallysubstituted by (C₁ -C₃) lower alkyl, halogen or (C₁ -C₃)-lower alkoxy;the moiety: ##STR6## is a five membered aromatic(unsaturated) fusednitrogen containing heterocyclic ring wherein D, E and F are selectedfrom carbon or nitrogen and wherein the carbon atoms may be optionallysubstituted by a substituent selected from halogen, (C₁ -C₃) loweralkyl, hydroxy, --COCl₃, --COCF₃, ##STR7## --CHO, amino, (C₁ -C₃) loweralkoxy, (C₁ -C₃) lower alkylamino, CONH-lower alkyl(C₁ --C₃),and-CON[lower alkyl (C₁ -C₃)]₂ ; q is one or two; R_(b) is independentlyselected from hydrogen, --CH₃ or --C₂ H₅ ; R³ is a moiety of theformula: ##STR8## wherein Ar is a moiety selected from the groupconsisting of ##STR9## wherein X is selected from O, S, NH, NCH₃ andNCOCH₃ ; R⁴ is selected from hydrogen, lower alkyl(C₁ -C₃), --CO--loweralkyl(C₁ -C₃), ##STR10## --SO₂ lower alkyl(C₁ --C₃); R¹ and R² areselected from hydrogen, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy andhalogen; R⁵ is selected from hydrogen, (C₁ -C₃) lower alkyl, (C₁ -C₃)lower alkoxy and halogen; R⁶ is selected from (a) moieties of theformulae: ##STR11## wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl,cyclohexenyl or cyclopentenyl; Ra is independently selected fromhydrogen, --CH₃, C₂ -C₅, ##STR12## --(CH₂)_(q) --O--lower alkyl (C₁ -C₃)and --CH₂ CH₂ OH, q is one or two, and R₁, R₂ and R_(b) are ashereinbefore defined; (b) a moiety of the formula: ##STR13## wherein R²is as hereinbefore defined; (c) a moiety of the formula: ##STR14##wherein J is R_(a), lower alkyl(C₁ -C₈) branched or unbranched, loweralkenyl(C₁ -C₈) branched or unbranched, O-lower alkyl(C₁ -C₈) branchedor unbranched, --O-lower alkenyl(C₁ -C₈) branched or unbranched,tetrahydrofuran, tetrahydrothiophene, or --CH₂ --K wherein K is (C₁ -C₃)lower alkoxy, halogen,, tetrahydrofuran, tetrahydrothiophene or theheterocyclic ring moiety: ##STR15## wherein D, E, F and G are selectedfrom carbon or nitrogen and wherein the carbon atoms may be optionallysubstituted with halogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-loweralkyl(C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, --CO₂ -lower alkyl(C₁ -C₃),and R_(a) and R_(b) are as hereinbefore defined; (d) a moiety of theformula: ##STR16## wherein R_(a) and R_(b) are as hereinbefore definedand Ar' is selected from moieties of the formula: ##STR17## wherein W'is selected from O, S, NH, N-lower alkyl (C₁ -C₃), NHCO-lower alkyl(C₁-C₃), and NSO₂ lower alkyl(C₁ -C₃); R⁷ is selected from hydrogen, loweralkyl (C₁ -C₃), halogen, O-lower alkyl (C₁ -C₃) and CF₃ ; R⁸ and R⁹ areindependently selected from hydrogen, lower alkyl(C₁ -C₃), --S-loweralkyl(C₁ -C₃), halogen, --NH-lower alkyl C₁ -C₃), --OCF₃, --OH, --CN,--S--CF₃, --NO₂, --NH₂, O-lower alkyl (C₁ -C₃), ##STR18## and CF₃ and;R¹⁰ is selected from hydrogen, halogen and lower alkyl(C₁ -C₃), and thepharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Within the group of the compounds defined by Formula I, certainsubgroups of compounds are broadly preferred. Broadly preferred arethose compounds wherein R₃ is the moiety: ##STR19## and Ar is selectedfrom the moiety ##STR20## wherein R⁵, R⁶ and R⁷ are as hereinbeforedefined.

Especially preferred are compounds wherein R³ is the moiety ##STR21## Aris selected from the moiety ##STR22## R⁶ is ##STR23## wherein cycloalkylis defined as C₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; R_(a)and R_(b) are as hereinbefore defined; and Ar' is selected from themoieties: ##STR24## wherein R⁸, R⁹ and W' are as hereinbefore defined.

Also especially preferred are compounds wherein Y in Formula I is--(CH₂)_(n) -- and n is zero or one; A--B is ##STR25## and R⁴, R⁵, R⁶,R⁷, R⁸, R⁹ and R¹⁰ are as hereinbefore defined; and m is an integer from1-2.

The most preferred of the compounds of Formula I are those wherein Y is--(CH₂)_(n) -- and n is one; A--B is ##STR26## R₃ is the moiety##STR27## Ar is the moiety ##STR28## R⁶ is ##STR29## --(CH₂)_(n)-cycloalkyl wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl,cyclohexenyl or cyclopentenyl; R_(a) and R_(b) are as hereinbeforedefined; and Ar' is ##STR30## wherein R⁵, R⁸ and R⁹ are as previouslydefined.

The most highly broadly preferred of the compounds of Formula I arethose wherein Y is --(CH₂)_(n) -- and n is zero or one; wherein themoiety ##STR31## is a fused phenyl, substituted phenyl, thiophene,furan, pyrrole or pyridine ring; A--B is ##STR32## m is one when n isone and m is two when n is zero; D, E, F, R¹, R², R⁴, R⁵, R⁷, R⁸, R⁹,R¹⁰, are as previously defined; R₃ is the moiety ##STR33## wherein Ar is##STR34## and R₆ is selected from the group ##STR35## where Ar' isselected from the group ##STR36## and W', R_(a), R_(b) and cycloalkylare as previously described.

More particularly preferred are compounds of the formulae: ##STR37##wherein the moiety: ##STR38## is selected from a phenyl, thiophene,furan, pyrrole or pyridine ring; R³ is the moiety: ##STR39## wherein Aris the moiety: ##STR40## R⁶ is ##STR41## and Ar' is selected from themoieties: ##STR42## wherein R_(a), R_(b), R⁵, R⁷, R⁸, R⁹, cycloalkyl andW' are as hereinbefore described; R¹¹ is selected from hydrogen,halogen, (C₁ -C₃) lower alkyl, hydroxy, ##STR43## --CHO, and (C₁ -C₃)lower alkoxy; and R¹² is selected from hydrogen, (C₁ -C₃) lower alkyl,halogen and (C₁ -C₃) lower alkoxy.

Also particularly preferred are compounds of the formulae: ##STR44##wherein m is one or two; the moiety: ##STR45## is selected from aphenyl, thiophene, furan, pyrrole or pyridine ring; R³ is the moiety:##STR46## wherein Ar is the moiety: ##STR47## (CH₂)_(n) cycloalkyl; Ar'is selected from the moieties: ##STR48## wherein R_(a), R_(b), R⁵, R⁶,R⁸, R⁹, cycloalkyl and W' are as hereinbefore defined; R¹¹ is selectedfrom hydrogen, halogen, (C₁ -C₃) lower alkyl, hydroxy, ##STR49## --CHO,and (C₁ -C₃) lower alkoxy; and R¹² is selected from hydrogen, (C₁ -C₃)lower alkyl, halogen and (C₁ -C₃) lower alkoxy.

More particularly preferred are compounds of the formulae: ##STR50## R³is the moiety: ##STR51## wherein Ar is the moiety: ##STR52## R⁶ is##STR53## wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl,cyclohexenyl or cyclopentenyl; R_(b) is hydrogen; R_(a) is independentlyselected from hydrogen, --CH₃, --C₂ H₅ or --(CH₂)_(q) N(CH₃)₂ ; Ar' isselected from the moieties: ##STR54## wherein q, R_(a), R_(b), R⁵, R⁷,R⁸, R⁹, R¹¹ and W' are as hereinbefore described; R¹² and R¹³ areindependently selected from hydrogen, (C₁ -C₃) lower alkyl, halogen,amino, (C₁ -C₃) lower alkoxy or (C₁ -C₃) lower alkylamino.

Also particularly preferred are compounds of the formulae: ##STR55##wherein m is one or two; R³ is the moiety: ##STR56## wherein Ar is themoiety: ##STR57## R⁶ is ##STR58## wherein cycloalkyl is defined as C₃-C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; R_(b) is hydrogen; R_(a)is independently selected from hydrogen, --CH₃, --C₂ H₅ or --(CH₂)_(q)N(CH₃)₂ ; and Ar' is selected from the moieties: ##STR59## wherein q,R⁵, R⁷, R⁸, R⁹, R¹¹ and W' are as hereinbefore defined; R¹² and R¹³ areindependently selected from hydrogen, (C₁ -C₃) lower alkyl, halogen,amino, (C₁ -C₃)lower alkoxy or (C₁ -C₃)lower alkylamino.

Compounds of this invention may be prepared as shown in Scheme I byreaction of tricyclic derivatives of Formula 3a and 3b with asubstituted or unsubstituted 4-nitrobenzoyl chloride 4 to give theintermediates 5a and 5b. Reduction of the nitro group in intermediates5a and 5b gives the 4-aminobenzoyl derivatives 6a and 6b. The reductionof the nitro group in intermediates 5a and 5b may be carried out undercatalytic reduction conditions (hydrogen-Pd/C; Pd/C- hydrazine-ethanol)or under chemical reduction conditions (SnCl₂ -ethanol; Zn-acetic acid;TiCl₃) and related reduction conditions known in the art for convertinga nitro group to an amino group. The conditions for conversion of thenitro group to the amino group are chosen on the basis of compatibilitywith the preservation of other functional groups in the molecule.

Reaction of compounds of Formula 6a and 6b with aroyl chloride orrelated activated aryl carboxylic acids in solvents such as chloroform,dichloromethane, dioxane, tetrahydrofuran, toluene and the like in thepresence of a tertiary base such as triethylamine anddiisopropylethylamine or pyridine and the like, affords the compounds 8aand 8b which are vasopressin antagonists. ##STR60##

Reaction of tricyclic derivatives of Formula 6a and 6b with either acarbamoyl derivative 9 or a isocyanate derivative 10 gives compounds(Scheme 2) of Formula 11a and 11b which are vasopressin antagonists ofFormula I wherein R⁶ is ##STR61##

Reaction of tricyclic derivatives of Formula 6a and 6b with arylaceticacids, activated as the acid chlorides 12, anhydrides, mixed anhydridesor activated with known activating reagents, gives compounds 13a and 13b(Scheme 3). ##STR62##

The compounds of Formula I wherein Y, A--B, Z, R¹, R² and R³ are asdefined and the Ar moiety of R³ (--COAr) is ##STR63## may be prepared,as shown in Scheme 4, by reacting an activated ester of theindole-5-carboxylic acids 14 with tricyclic derivatives 3a and 3b. Theindole-5-carboxylic acids 14 may be activated by preparing theanhydride, a mixed anhydride or reacting with diethyl cyanophosphonate,N,N-carbonyldiimidazole or related peptide coupling reagents. As anexample, the derivative 15 may be prepared by the acid 14 andN,N-carbonyldiimidazole in tetrahydrofuran; the solvent is removed andthe derivative reacted with 3a or 3b at 100° C. to 120° C. without asolvent. Alternatively, 3a and 3b may be reacted with 5 in a solventsuch as toluene or xylene at reflux temperatures. The activating reagentfor the indole acids 14 is chosen on the basis of its compatibility withthe R⁴ group and its reactivity with the tricyclic derivatives 3a and 3bto give the vasopressin antagonists 16a and 16b. ##STR64##

The compounds of Formula I wherein Y, A--B, Z, R¹, R² and R³ are asdefined and the Ar moiety of R³ (--COAr) is ##STR65## wherein R⁶ is##STR66## may be prepared as shown in Scheme 5 by first convertingderivatives 8a and 8b into the intermediates 17a and 17b and thenreacting these intermediates with sodium or lithium azide to give theproducts 18a and 18b. ##STR67##

Alternatively, the products 18a and 18b may be prepared by couplingtetrazole derivatives of the Formula 19 with tricyclic derivatives 3aand 3b (Scheme 6). The tetrazole carboxylic acids are activated forcoupling to the tricyclic compounds 3a and 3b by reaction with peptidecoupling reagents, by conversion to the acid chlorides, anhydrides ormixed anhydrides. ##STR68##

As an alternative method for synthesis of compounds of this invention asdepicted in Formula I wherein Y, A--B, D, E, F and Z are as previouslydescribed and R³ is ##STR69## is the coupling of aryl carboxylic acids20 with the tricyclic derivatives 3a and 3b to give 21a and 21b.

The aryl carboxylic acids are activated for coupling by conversion to anacid chloride, bromide or anhydride or by first reacting with anactivating reagent such as N,N-dicyclocarbodiimide, diethylcyanophosphonate and related "peptide type" activating reagents. Themethod of activating the acids 20 for coupling to the tricyclicderivatives 3a and 3b is chosen on the basis of compatibility with othersubstituent groups in the molecule. The method of choice is theconversion of the aryl carboxylic acids 20 to the corresponding aroylchloride. The aryl acid chlorides 22may be prepared by standardprocedures known in the art, such as reaction with thionyl chloride,oxalyl chloride and the like. The coupling reaction is carried out insolvents such as halogenated hydrocarbons, toluene, xylene,tetrahydrofuran dioxane in the presence of pyridine or tertiary basessuch as triethylamine and the like (Scheme 7). Alternatively, the aroylchlorides 22, prepared from the aryl carboxylic acids 20, may be reactedwith derivatives 3a and 3b in pyridine with or without4-(dimethylamino)pyridine.

In general, when the aryl carboxylic acids 20 are activated withN,N,-carbonyldiimidazole and other "peptide type" activating reagents,higher temperatures are required than when the aroyl chlorides are used.The reaction may be carried out in a higher boiling solvent xylene orwithout a solvent (100° C. to 150° C.). ##STR70##

The starting materials 3a and 3b in the foregoing Schemes 1-7 may beprepared as follows. In accordance with Scheme 8, alkylation ofheterocycles of structural type 24 with an alkylating moiety such as 23gives intermediates 25. The heterocycle 24 may contain anα-carboxaldehyde function or an α-carboxylic and/or ester function asshown in Scheme 8. Where the intermediate 25 (R¹⁵ ═H) contains anα-carboxaldehyde group, hydrogenation with palladium-on-carbon givesreduction and ring closure in one step to give 29.

In derivatives 25 where R¹⁵ is an α-carboxylic and/or an α-carboxylicester function, the intermediate amino acid derivative 27 is firstisolated and then ring closed. The ring closure of derivatives 27 may becarried out by heating or by activation of the acid function (27:R¹⁵ ═H)for ring closure. The cyclic lactams 28 are conveniently reduced withdiborane or lithium aluminum hydride to give intermediates 29. Reactionof tricyclic derivatives 29 with aroyl chlorides (ArCOCl), where Ar isas hereinbefore defined, gives diazepines 26.

Tricyclic derivatives of structural type 36 may be prepared as shown inScheme 9. Formylation of 32 under known conditions in the literature,such as Vilsmeier formylation, gives intermediates 35which on reductionand ring closure affords tricyclics 37.

Where Z is a fused substituted or unsubstituted phenyl group, theprocedure gives pyrrolo[1,2-a]quinoxalines 36. These derivatives 36 and37 may be reacted with aroyl chlorides (ArCOCl) wherein Ar is aspreviously defined or with a substituted or unsubstituted 4-nitrobenzoylchloride or with a nitrogen protecting group, such as benzyloxycarbonylchloride to give compounds 38 and 39. The compounds 38 and 39 may bereacted with chlorine, bromine or halogenating reagents such asN-chlorosuccinimide, N-bromosuccinimide and the like to give compounds40 and 41 wherein R¹⁷ is a halogen atom. The derivatives 38 and 39 maybe formylated and acetylated to give products 40 and 41 wherein R¹⁷ is aCHO or a --COCH₃ group. Halogenation, formylation and acetylation ofderivatives 36 gives 1-substituted pyrrolo[1,2-a]quinoxalines. Thederivatives 38, 39, 40 and 41 wherein R¹⁶ is a substituted orunsubstituted 4-nitrobenzoyl group are reduced to give the4-aminobenzoyl derivatives 42d and 43d which are reacted with reagentsAr'COCl, Ar'CH₂ COCl or ##STR71## wherein Ar' and R_(b) are aspreviously hereinbefore defined, to give tricyclic diazepines 44 and 45.##STR72##

The compounds of this invention wherein R³ is the moiety: ##STR73## andthe Ar group is the moiety: ##STR74## and R⁶ is a ##STR75## group,wherein R_(a), R⁵, R⁷ and Ar' are as previously hereinbefore defined,are synthesized as shown in Scheme 10. The tricyclic derivatives 46 and47 are reacted with the mono methyl terephthaloyl chloride 48 to givethe aroylated methyl ester compounds 49 and 50. Hydrolysis of the methylesters 49 and 50 gives the acids 51 and 52 which are activated forcoupling by conversion to an activated ester or converted to the acidchlorides 53 and 54. Reaction of the acid chlorides 53 and 54with theamines, ##STR76## wherein R_(a) and Ar' are as hereinbefore definedgives the derivatives 55 and 56. ##STR77##

Preparation of some tricyclic diazepines useful for starting materialsfor the synthesis of compounds of this invention are shown in Schemes 8and 9. Other tricyclic diazepines are prepared by literature proceduresor by methods known in the art or by procedures reported for thesynthesis of specific known tricyclic diazepines. These diazepine ringsystems discussed below when subjected to reaction conditions shown inSchemes 1, 2, 3, 4, 5, 6, 7, 9 and 10 give the compounds of thisinvention.

The tricyclic diazepine ring system,10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, ##STR78## isreported by G. Stefancich, R. Silvestri and M. Artico, J. Het. Chem. 30,529(1993); ring substitution on the same ring system is reported by G.Stefancich, M. Artico, F. Carelli, R. Silvestri, G. deFeo, G. Mazzanti,I. Durando, M. Palmery, IL Farmaco, Ed. Sc., 40, 429(1985). ##STR79##

The synthesis of9,10-dihydro-4H-furo[2,3-e]-pyrrolo[1,2-a][1,4]diazepin-9-one ##STR80##is reported by F. Povazunec, B. Decroix and J. Morel, J. Het. Chem. 29,1507(1992) and is reduced to give the tricyclic heterocycle9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine. ##STR81##

The tricyclic 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine ringsystem is reported by L. Cecchi and G. Filacchioni, J. Het. Chem., 20,871(1983); ##STR82##

The synthesis of9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine isreported by A. Daich and B. Decroix, Bull. Soc. Chim. Fr 129, 360(1992);##STR83## and is reduced with boron-dimethylsulfide to give9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. ##STR84##

Also reported by A. Daich and B. Decroix is 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine ##STR85## which is also reduced togive 4,10-dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine ##STR86##

Reported by B. Decroix and J. Morel, J. Het. Chem., 28, 81(1991) arepyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine; ##STR87## andpyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. Reduction by hydrogen-Pd/c orchemical reduction with reagents such as sodium cyanoborohydride andacetic acid gives the dihydro tricyclic heterocycles ##STR88##

The synthesis of the tricyclic 1,5-benzodiazepine ring system,6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine, has been reported byF. Chimenti, S. Vomero, R. Giuliano and M. Artico, IL Farmaco, Ed. Sc.,32, 339(1977). Annelated 1,5-benzodiazepines containing five memberedrings have been reviewed by A. Chimirri, R. Gitto, S. Grasso, A. M.Monforte, G. Romeo and M. Zappala, Heterocycles, 36, No. 3, 604(1993),and the ring system 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine isdescribed. ##STR89##

The preparation of5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-ones from1,2-di-hydro-3H-4-dimethylamino-l,5-benzodiazepin-2-ones has beendescribed by M. DiBroccio, G. Roma, G. Grossi, M. Ghia, and F. MattioliEur. J. Med. Chem; 26, 489(1991). Reduction of5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-ones withdiborane or lithium hydride gives the tricyclic 5,6-dihydro derivatives.##STR90##

The compounds of this invention and their preparation can be understoodfurther by the following examples, but should not constitute alimitation thereof.

Most particularly preferred are compounds selected from those of theformula: ##STR91## wherein Y is a moiety --(CH₂)--; A--B is a moiety:##STR92## the moiety ##STR93## represents: (1) fused phenyl or fusedsubstituted phenyl optionally substituted by one or two substituentsselected from (C₁ -C₃) lower alkyl, halogen, amino, (C₁ -C₃) loweralkoxy and (C₁ -C₃) lower alkylamino; the moiety: ##STR94## is a fivemembered aromatic(unsaturated) fused nitrogen containing heterocyclicring wherein D, E and F are carbon and wherein the carbon atoms may beoptionally substituted by a substituent selected from halogen, (C₁ -C₃)lower alkyl, ##STR95## and amino; q is one or two; R_(b) isindependently selected from hydrogen, --CH₃ or --C₂ H₅ ; R³ is a moietyof the formula ##STR96## wherein Ar is a moiety: ##STR97## R⁵ isselected from hydrogen, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy andhalogen; R⁶ is a moiety of the formula: ##STR98## R_(a) is hydrogen;wherein Ar' is a moiety of the formula: ##STR99## R⁷ is selected fromhydrogen, lower alkyl(C₁ -C₃), halogen, O-lower alkyl(C₁ -C₃) and CF₃ ;R⁸ and R⁹ are independently selected from hydrogen, lower alkyl(C₁ -C₃),--S-lower alkyl(C₁ -C₃), halogen, --NH-lower alkyl(C₁ -C₃),--OCF₃, --OH,--CN, --S--CF₃, --NO₂, --NH₂, O-loweralkyl(C₁ -C₃), CF₃ and ##STR100##and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

EXAMPLE 1N-[4-(5H-Pyrrolo[2,1-c]][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]2,3-difluorobenzamide

To a stirred solution of 0.350 g of 2,3difluorobenzoyl chloride in 5 mlof methylene chloride is added 0.346 ml of triethylamine. After stirringfor 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 72 hours. The reaction mixture isfiltered and the solid washed with methylene chloride. The solid issaved. The combined filtrate is washed with water, 2N citric acid, 1MNaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filteredand evaporated in vacuo to give 100 mg of a solid. The two solids arecombined and dried to afford 790 mg of the desired product as a solid,m.p. 252°-258° C.

EXAMPLE 2N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-methoxybenzamide

To a stirred solution of 0.362 g of 2-methoxybenzoyl chloride 5 ml ofmethylene chloride is added 0.346 g of triethylamine at 0° C. Afterstirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 18 hours at room temperature. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, 1M NaHCO₃, and brine. The reaction mixtureis dried with Na₂ SO₄, filtered through hydrous magnesium silicate andevaporated in vacuo to give a solid which is purified by crystallizationfrom ethyl acetate to give 0.430 g of the desired product as acrystalline solid, m.p. 185°-188° C.

EXAMPLE 32-Methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzamide

To a mixture of 1.93 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in15 ml of methylene chloride, cooled to 0° C. is added 1.13 ml oftriethylamine. After stirring for 3 minutes, a mixture of 1.0 g of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylenechloride is added. The cooling bath is removed and after about 30minutes a complete solution is obtained. The reaction mixture is allowedto stir at room temperature for 48 hours and the volatiles areconcentrated in vacuo to a residue. The residue is dissolved in 100 mlof ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO₃and brine. The solution is dried with Na₂ SO₄ and the volatilesconcentrated in vacuo to give 3.0 g of a residue. A 300 mg sample of theresidue is purified by thick layer chromatography using 10% ethylacetate-methylene chloride to give 160 mg of the desired product. Theremainder of the crude material is purified by flash chromatographyusing 10% ethyl acetate in methylene chloride to give the desiredproduct as a residue which is crystallized from ethyl acetate to give800 mg of the desired product as white crystals, m.p. 212°-215° C.

EXAMPLE 4N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,5-dichlorobenzamide

To a solution of 414.5 mg of 2,5-dichlorobenzoyl chloride in 5 ml ofmethylene chloride is added 276 μl of triethylamine. After stirring at0° C. for 3 minutes 400 mg of the10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added. The bath is removed and the reaction mixture stirred at roomtemperature for 3 hours. The volatiles are concentrated in vacuo to givea residue which is dissolved in ethyl acetate and washed with water, 2Ncitric acid, 1M NaHCO₃ and brine. The organic layer is dried with Na₂SO₄ and concentrated in vacuo to a residue which is purified by thicklayer chromatography by elution with 1:1 ethyl acetate-hexanes to give aresidue. The residue is crystallized from ethyl acetate to give 220 mgof the desired product as white crystals, m.p. 218°-220° C.

EXAMPLE 5N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin10(11H)-ylcarbonyl)phenyl]-3-methyl-2-thiophenecarboxamide

To a solution of 318 mg of 3-methyl-2-thiophenecarbonyl chloride in 5 mlof methylene chloride at 0° C. is added 346 μl of triethylamine. Afterstirring for 3 minutes, 500 mg of the10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added. The bath is removed and the reaction mixture stirred at roomtemperature for 18 hours. The volatiles are concentrated in vacuo togive a residue which crystallizes from ethyl acetate to afford 800 mg ofsolid. The solid is dissolved in methylene chloride washed with water,2N citric acid, 1M NaHCO₃ and brine. The organic layer is filteredthrough hydrous magnesium silicate, dried with Na₂ SO₄ and concentratedin vacuo to give a residue which crystallizes from ethyl acetate toafford 400 mg of the desired product as a white solid, m.p. 232°-235° C.

EXAMPLE 6N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide

To a solution of 415 mg of 2,4-dichlorobenzoyl chloride in 5 ml ofmethylene chloride at 0° C. is added 346 μl of triethylamine. Afterstirring for 3 minutes, 500 mg of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added. The bath is removed and the reaction mixture stirred at roomtemperature for 18 hours. The volatiles are concentrated in vacuo togive a residue which is dissolved in ethyl acetate, washed with water,2N citric acid, 1M NaHCO₃ and brine. The organic layer is dried with Na₂SO₄, filtered and concentrated in vacuo to give a residue which iscrystallized from ethyl acetate to give 420 mg of the desired product asa crystalline solid, m.p., 210°-212° C.

EXAMPLE 7N[4-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chlorobenzamide

To a solution of 347 mg of 2-chlorobenzoyl chloride in 5 ml of methylenechloride at 0° C. is added 346 μl of triethylamine. After stirring for 3minutes, 500 mg of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added. The bath is removed and the reaction mixture stirred at roomtemperature for 18 hours. The volatiles are concentrated in vacuo togive a residue which is dissolved in methylene chloride, washed withwater, 2N citric acid, 1M NaHCO₃ and brine. The organic layer is driedwith Na₂ SO₄, filtered and concentrated in vacuo to give a residue whichis crystallized from methylene chloride to give 525 mg of the desiredproduct as a white crystalline solid, m.p. 228°-230° C.

EXAMPLE 8N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin10(11H)-ylcarbonyl)phenyl]-2-fluorobenzamide

To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylenechloride at 0° C. is added 346 μl of triethylamine. After stirring for 3minutes, 500 mg of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added. The bath is removed and the reaction mixture stirred at roomtemperature for 18 hours. The volatiles are concentrated in vacuo togive a residue which is dissolved in methylene chloride, washed withwater, 2N citric acid, 1M NaHCO₃ and brine. The organic layer is driedwith Na₂ SO₄, filtered and concentrated in vacuo to give 620 mg of thedesired product as a crystalline solid, m.p. 257°-260° C.

EXAMPLE 92-Chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

A mixture of 0.273 g of 2-chlorophenylacetic acid is stirred at roomtemperature for 2 hours. The volatiles are evaporated in vacuo to aresidue which is distilled with toluene several times. The residue isdissolved in 10 ml of methylene chloride containing 0.26 ml oftriethylamine and while stirring 0,485 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineadded. The reaction mixture is stirred at room temperature for 18 hours.The volatiles are removed and the residue dissolved in ethyl acetatewhich is washed with water, 1N HCl, 1M NaHCO₃ and brine. The organiclayer is dried and evaporated to a residue which is purified by flashchromatography using 1:1 ethyl acetate-hexane to give the desiredproduct as a yellow solid, m.p. 99°-103° C.

EXAMPLE 10 1-(2-Nitrophenyl)-1H-pyrrole-2-carboxaldehyde

To a solution of 3.76 g of 1-(2-nitrophenyl)pyrrole in 20 ml ofN,N-dimethylformamide at 0° C. is added dropwise with stirring 3 ml ofphosphorus oxychloride. Stirring is continued for 30 minutes and thereaction mixture is heated at 90° C. for 1 hour. After cooling to roomtemperature the mixture is treated with crushed ice and the pH adjustedto 12 with 2N sodium hydroxide. The resulting suspension is filtered,washed with water and dried to give 5.81 g of the desired product as alight yellow solid m.p. 119°-122° C.

EXAMPLE 11 4,5-Dihydro-pyrrolo-[1,2-a]-quinoxaline

To a solution of 1.0 g of 1-(2-nitrophenyl)-1H-pyrrole-2-carboxaldehydein 40 ml of ethyl alcohol and 40 ml of ethyl acetate, under argon, isadded 40 mg of 10% Pd/C. The mixture is hydrogenated at 40 psi for 2hours and filtered through diatomaceous earth. The filtrate isconcentrated in vacuo to a residue which is dissolved in ether andtreated with hexanes to give 0.35 g of the desired product as a beigesolid m.p. 108°-110° C.

EXAMPLE 12

4-[(2-Methylbenzoyl)amino]benzoic acid

A mixture of 43.42 g of ethyl 4-aminobenzoate and 40.8 g of2-methylbenzoyl chloride in 150 ml of dichloromethane is cooled in anice bath and 26.56 g of triethylamine is added dropwise. After theaddition, the solution is stirred at room temperature overnight. Themixture is poured into water and the organic layer separated. Theorganic layer is washed with water, 1N HCl, 1M NaHCO₃ and dried over Na₂SO₄. The solvent is removed and the solid slurried with ethyl acetateand filtered to give 57 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate ascrystals, m.p. 110°-115° C. A mixture of 50.7 g of the precedingcompound in 280 ml of ethyl alcohol and 55 ml of 10N NaOH is refluxedfor 5 minutes. The mixture is cooled to room temperature, diluted with200 ml of water and acidified with concentrated hydrochloric acid (pH1-2). The mixture is filtered and the solid washed with water and driedto give 51 g of the desired product as white crystals, m.p. 270°-275° C.

EXAMPLE 13 4-[(2-Methylbenzoyl)amino]benzoyl chloride

A mixture of 10.3 g of 4-[(2-methylbenzoyl)amino]benzoic acid and 32 mlof thionyl chloride is refluxed for 1.5 hours. The solution isconcentrated in vacuo. Toluene is added and the solvent removed invacuo. Toluene is added and the mixture chilled and filtered to give thedesired product as a yellow solid, 135°-141° C.

EXAMPLE 14 2-Methyl-N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]benzamide

A mixture of 0.51 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride and0.36 g of 1,1'-carbonyldiimidazole in 6 ml of tetrahydrofuran is stirredat room temperature for 1 hour. To the reaction mixture is added 0.17 gof 4,5-dihydropyrrolo-[1,2-a]-quinoxaline followed by heating at refluxfor 60 hours. The volatiles are concentrated vacuo to a residue which isdissolved in ethyl acetate. The organic layer is washed with 1N HCl, 1MNaHCO₃, brine, dried with Na₂ SO₄ and filtered through hydrous magnesiumsilicate. The volatiles are concentrated in vacuo to a residue which ischromatographed by elution with 1:2 ethyl acetate-hexanes to give 0.14 gof the desired product as a white solid, m.p. 206°-207° C.;

MASS SPEC (CI) 408 (MH⁺).

                  TABLE I                                                         ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 14 with the                                         appropriately substituted aroyl chloride                                      Example                                                                       No.         Compound                                                          ______________________________________                                        15          N-[4-(pyrrolo[1,2-a]quinoxalin-                                               5(4H)-ylcarbonyl)phenyl]-2-                                                   chlorobenzamide                                                   16          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,5-dichloro-                                              benzamide                                                         17          N-[4-(pyrrolo(1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,4-dichloro-                                              benzamide, m.p. 200°-202° C.                        18          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-chloro-4-methyl-                                         benzamide                                                         19          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methyl-4-chloro-                                         benzamide                                                         20          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,4-dimethyl-                                              benzamide                                                         21          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,3-dimethyl-                                              benzamide, m.p. 216°-220° C.                        22          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methoxy-                                                 benzamide                                                         23          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-trifluoro-                                               methoxybenzamide                                                  24          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,4-dimethoxy-                                             benzamide                                                         25          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,6-dimethoxy-                                             benzamide                                                         26          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]benzamide                                       27          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,6-dichloro-                                              benzamide                                                         28          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,6-dimethyl-                                              benzamide                                                         29          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl)-2-(methylthio)-                                            benzamide                                                         30          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methyl-3-                                                thiophenecarboxamide                                              31          N-[4-(pyrrolo[1,2-a]quinoxalln-5(4H)-                                         ylcarbonyl)phenyl]-3-methyl-2-                                                thiophenecarboxamide                                              32          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methyl-3-                                                furanecarboxamide                                                 33          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-3-methyl-2-                                                furanecarboxamide                                                 34          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]benzeneacetamide                                35          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-chlorobenzene-                                           acetamide                                                         36          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methylbenzene-                                           acetamide (yellow foam); Anal. Calc'd                                         for C.sub.27 H.sub.23 N.sub.3 O.sub.2 : C, 76.9; H, 5.5; N,                   10.0; Found: C, 75.6; H, 6.0; N, 9.4                              37          N-(4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methyl-3-                                                thiopheneacetamide                                                ______________________________________                                    

EXAMPLE 38 N-(2-Nitrobenzoyl)pyrrole-2-carboxaldehyde

To an ice bath cooled solution of 5.6 g of 2-pyrrolecarboxaldehyde in 40ml of tetrahydrofuran is added 2.4 g of 60% sodium hydride in mineraloil. The temperature elevates to 40° C. After stirring for 20 minutes asolution of 11.0 g of 2-nitrobenzoyl chloride in 20 ml oftetrahydrofuran is added dropwise over 20 minutes. After stirring in thecold for 45 minutes, the reaction mixture is poured into ice water andether then filtered. The cake is washed with additional ether. The twophase filtrate is separate and the ether layer dried and concentrated invacuo to give 10 g of a residue as a dark syrup which is scratched withethanol to give crystals which are collected by filtration, washed withether and then dried to afford 3.2 g of solid, m.p. 95°-99° C.

EXAMPLE 39 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

A mixture of 1.5 g of N-(2-nitrobenzoyl)-pyrrole-2-carboxaldehyde in 50ml of ethyl acetate, 2 drops of concentrated HCl and 0.3 g of 10% Pd/Cis shaken in a Parr apparatus under hydrogen pressure for 1.75 hours.The mixture is filtered, 0.4 g of 10% Pd/C added and the mixture shakenin a Parr apparatus under hydrogen pressure for 2 hours. The reactionmixture is filtered through diatomaceous earth and the filtrateconcentrated in vacuo to give 1.0 g of a yellow oil. The residue ispurified on thick layer chromatography plates by elution with 4:1 ethylacetate:hexane to give 107 mg of the desired product as an oily solid.

EXAMPLE 40 2-Methyl-N-[4-[(5-oxo-5H-pyrrolo[2,1-c]-[1,4]benzodiazepin10(11H)-yl)carbonyl]phenyl]benzamide

To a stirred solution of 107 mg of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one in 3 ml ofmethylene chloride containing 0.084 ml of triethylamine is added 165 mgof 4-[(2-methylbenzoyl)amino]benzoyl chloride and stirring continued for6 hours. The volatiles are removed in vacuo to a residue which ispurified on thick layer chromatography plates with 7:3 hexane-ethylacetate to afford the desired product as a foam.

EXAMPLE 41N-[4-(3-Chloro-5H-pyrrolo[2,1c][1,4]benzodiazepine10(11H)ylcarbonyl)phenyl]-2-methylbenzamide

To an ice-water cooled suspension of 211 mg of2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzamidein 5 ml of tetrahydrofuran is added 67 mg of N-chlorosuccinimidefollowed by continued stirring in the cold for 10 minutes. The bath isremoved and stirring continued for 2.25 hours. The reaction mixture isadded to ice-water and extracted with ether. The organic layer is driedand concentrated in vacuo to give a foam which is crystallized fromethyl acetate-hexane to give 157 mg of the desired product as anorange-pink solid, m.p. 185°-187° C.

EXAMPLE 422-Methyl-N-[4-(1-chloropyrrolo[1,2-a]quinoxalin-5)4H)-ylcarbonyl)phenyl]benzamide

To an ice-water cooled suspension of 5 mmol of2-methyl-N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)-phenyl]benzamidein 5 ml of tetrahydrofuran is added 5.5 mmol of N-chlorosuccinimidefollowed by continued stirring in the cold for 10 minutes. The bath isremoved and stirring continued for 2.25 hours. The reaction mixture isadded to ice-water and extracted with ether. The organic layer is driedand concentrated in vacuo to give the desired product as a solid.

                  TABLE II                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 42.                                                 Example                                                                       No.           Compound                                                        ______________________________________                                        43            2-chloro-N-[4-(1-chloropyrrolo-                                               [1,2-a]quinoxalin-                                                            5(4H)-ylcarbonyl)phenyl]-                                                     benzamide                                                       44            2,4-dichloro-N-[4-(1-chloro-                                                  pyrrolo-[1,2-a]quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl]-                                                     benzamide                                                       45            2,5-dichloro-N-[4-(1-chloro-                                                  pyrrolo-[1,2-a]quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl]-                                                     benzamide                                                       46            2,3-dimethyl-N-[4-(1-chloro-                                                  pyrrolo-[1,2-a]quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl]-                                                     benzamide                                                       47            2,4-dimethyl-N-[4-(1-chloro-                                                  pyrrolo-[1,2-a]quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl]-                                                     benzamide                                                       48            2,5-dimethyl-N-[4-(1-chloro-                                                  pyrrolo-[1,2-a]quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl]-                                                     benzamide                                                       ______________________________________                                    

EXAMPLE 493-Chloro-10,11-dihydro-10-(4-nitrobenzoyl-5H-pyrrolo[2,1-c][1,4]-benzodiazepine

To an ice-water cooled solution of 250 mg of10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in6 ml of tetrahydrofuran is added 100 mg of N-chlorosuccinimide. Thereaction mixture is stirred in the cold for 30 minutes and at roomtemperature for 2 hours. The reaction mixture is poured into ice water,stirred for 5 minutes and extracted with ether. The organic layer isdried and concentrated in vacuo to give 0.2 g of a yellow foam.Trituration with ethyl alcohol gives 66 mg of the desired product as ayellow solid, m.p. 119°-125° C.

EXAMPLE 503-Chloro-10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 1 mmol of3-chloro-10,11-di-hydro-10-(4-nitroaminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine,2.5 mmol of anhydrous hydrazine, 50 mg of palladium on carbon and 10 mlof ethyl alcohol is refluxed for 1.5 hours. The mixture is filteredthrough diatomaceous earth and the filtrate concentrated to dryness togive the desired product as a solid.

EXAMPLE 51N-[4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-methylbenzamide

A mixture of 1 mmol of3-chloro-10,11-di-hydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine,2 mmol of triethylamine, and 1.1 mmol of 2-methylbenzoylchloride in 8 mlof dichloromethane is stirred at room temperature overnight. The mixtureis washed with water, and 1M NaHCO₃ and dried(Na₂ SO₄). The solvent isremoved in vacuo to give a solid which is recrystallized fromdichloromethane-hexane to give crystals, 185°-187° C.

                  TABLE III                                                       ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 51 with the                                         appropriately substituted aroyl chloride                                      Example                                                                       No.         Compound                                                          ______________________________________                                        52          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             (1,4)benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-chlorobenzamide                                53          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2,5-dichloro-                                                benzamide                                                         54          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2,4-dichloro-                                                benzamide (solid foam), Anal.                                                 Calc'd for C.sub.26 H.sub.18 Cl.sub.3 N.sub.3 O.sub.2 : C,                    61.1;                                                                         H, 3.6; N, 8.2; Cl, 20.8; Found:                                              C, 60.0; H, 3.5; N, 7.7; Cl, 20.3                                 55          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-fluoro-                                                    benzamide                                                         56          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-chloro-4-                                                  methylbenzamide                                                   57          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-methyl-4-                                                  chlorobenzamide                                                   58          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2,4-dimethyl-                                                benzamide                                                         59          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2,3-dimethyl-                                                benzamide                                                         60          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-methoxy-                                                   benzamide                                                         61          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-trifluoro-                                                 methoxybenzamide                                                  62          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2,4-dimethoxy-                                               benzamide                                                         63          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2,6-dimethoxy-                                               benzamide                                                         64          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]benzamide                                         65          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             (1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2,6-dichloro-                                                benzamide                                                         66          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2,6-dimethyl-                                                benzamide                                                         67          N-[4-(3-Chloro-5H-pyrrolo(2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-methylthio-                                                benzamide                                                         68          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-methyl-3-                                                  thiophenecarboxamide                                              69          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-3-methyl-2-                                                  thiophenecarboxamide                                              70          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-methyl-3-                                                  furanecarboxamide                                                 71          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-3-methyl-2-                                                  furanecarboxamide                                                 72          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]phenylacetamide                                   73          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-chlorophenyl-                                              acetamide                                                         74          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl)-2-methylbenzene-                                             acetamide                                                         75          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-methyl-3-                                                  thiopheneacetamide                                                76          N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl]-2-methyl-3-                                                  furanacetamide                                                    ______________________________________                                    

EXAMPLE 77 1-(2-Nitrobenzyl)-2-pyrrolecarboxaldehyde

To 5.56 g of 60% sodium hydride in mineral oil, washed three times withhexane, is added 300 ml of N,N-dimethylformamide under argon. Thereaction mixture is cooled in an ice-bath and 13.2 g ofpyrrole-2-carboxaldehyde is added slowly. The reaction mixture becomes acomplete solution and is stirred for an additional 10 minutes. Whilestirring, 30.0 g of 2-nitrobenzyl bromide is added slowly. Aftercomplete addition, the reaction mixture is stirred for 30 minutes, theice bath is removed and the reaction mixture stirred at room temperaturefor 24 hours. The N,N-dimethylformamide is concentrated in vacuo to givea residue which is stirred with ice water for 1 hour. The resultingsolid is collected, air dried, then vacuum dried to give 30.64 g of thedesired product as a tan solid, m.p. 128°-132° C.

EXAMPLE 78 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 30.6 g of 1-(2-nitrobenzyl)-2-pyrrolecarboxaldehyde and3.06 g of 10% Pd/C in 400 ml of ethyl acetate and 400 ml of ethylalcohol is hydrogenated over 18 hours. The reaction mixture is filteredthrough diatomaceous earth and the filtrate is treated with activatedcarbon and filtered through diatomaceous earth. The filtrate isconcentrated in. vacuo to give a residue which is dissolved in methylenechloride containing ethyl alcohol. The solution is passed through a padof silica gel and the pad washed with a 7:1 hexane-ethyl acetatesolution to give 16.31 g of the desired product as solid, m.p. 145°-148°C.

EXAMPLE 7910,11-Dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 3.3 g of10,11-dihydro-5H-yrrolo[2,1-c][1,4]benzodiazepine in 50 ml of methylenechloride under argon is added 5.0 ml of triethylamine followed by icebath cooling. A solution of 4.0 g of 4-nitrobenzoyl chloride in 20 ml ofmethylene chloride is added dropwise. Following complete addition, theice bath is removed and the reaction mixture stirred at room temperaturefor 2 hours. The volatiles are removed in vacuo to give a residue whichis dissolved in ethyl acetate. The solution is washed with water, 1NHCl, NaHCO₃, brine, dried with Na₂ SO₄ and filtered. The filtrate isconcentrated in vacuo to a solid which is dissolved in methylenechloride, passed through silica gel and the pad washed with ethylacetate. The combined filtrate is concentrated in vacuo to give 5.3 g ofthe desired product as a yellow solid, m.p. 188°-190° C.

EXAMPLE 8010,11-Dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 2.00g of10,11-dihydro-10(4-itrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in15 ml of ethyl alcohol and 15 ml of ethyl acetate containing 0.2 g of10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filteredthrough a pad of diatomaceous earth. The filtrate is concentrated invacuo to a solid which is dissolved in methylene chloride, passedthrough silica gel and the pad washed with 3:1 ethyl acetate-hexane. Thefiltrate is concentrated in vacuo to give 1.5 g of the desired productas a yellow solid, m.p. 166°-168° C.

EXAMPLE 8110,11-Dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 21.58 g of10,11-dihydro-10-(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 325 ml of ethyl alcohol is added 2.15 g of 10% Pd/C and 5.16 g ofhydrazine followed by stirring and heating under reflux for 15 hours.The room temperature reaction mixture is filtered through diatomaceousearth. The filtrate is concentrated in vacuo to a solid which isdissolved in methylene chloride and passed through a pad of hydrousmagnesium silicate. The filtrate is concentrated in vacuo to give 19.2 gof the desired product as a tan solid. The solid is purified by flashchromatography using 7:1 ethyl acetate-hexane to give 17.97 g of thedesired product, m.p. 166°-168° C.

EXAMPLE 82N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-3-chlorobenzo[b]thiophene-2-carboxamide

To a stirred solution of 0,440 g of 3chlorobenzo[b]thiophen-2-carbonylchloride in 10 ml of methylene chloride is added 0.:33 ml oftriethylamine. After stirring for 15 minutes, 0.485 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 18 hours. The reaction mixture iswashed with water, 1N HCl, NaCHO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography using 1:1 ethyl acetate-hexaneto give 0.49 g of solid, m.p. 220°-222° C.

EXAMPLE 83N-4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,3-dimethylbenzamide

To a stirred solution of 0.320 g of 2,3-dimethylbenzoyl chloride in 10ml of methylene chloride is added 0.33 ml of triethylamine. Afterstirring for 15 minutes, 0. 485 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 5 hours. The reaction mixture iswashed with water, 1N HCl, NaCHO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography using 1:1 ethyl acetate-hexaneto give 0.39 g of solid, m.p. 168°-170° C.

EXAMPLE 84N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-ethoxybenzamide

To a stirred solution of 0.362 g of 2-ethoxybenzoyl chloride 5 ml ofmethylene chloride is added 0.346 g of triethylamine at 0° C. Afterstirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 72 hours at room temperature. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, NaCHO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography using 1:1 ethyl acetate-hexaneto give 0.890 g of solid which is crystallized from ethyl acetate togive 0.540 g of the desired product as a white solid, m.p. 160°-176° C.

EXAMPLE 85N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(methylthio)benzamide

To a stirred solution of 0.364 g of 2-(methylthio)benzoyl chloride 5 mlof methylene chloride is added 0.346 g of triethylamine at 0° C. Afterstirring for 3 minutes, 500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 72 hours at room temperature. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, NaCHO₃, and brine. The reaction mixture isdried with Na₂ S04, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography using 1:1 ethyl acetate-hexaneto give a solid which is crystallized from ethyl alcohol to give 0.480 gof the desired product as a white solid, m.p. 171°-174° C.

EXAMPLE 86 3-Methylbenzo[b]thiophene-2-acetyl chloride

A mixture of 2.0 g of 3-methylbenzo[b]thiophene-2-acetic acid and 19.4ml of thionyl chloride is heated at reflux for 1 hour. The volatiles areevaporated in vacuo to give a residue which is concentrated from toluenethree times and dried under vacuum to give 2.25 g of the desired productas a residue.

EXAMPLE 87N-[4-(5H-Pyrrolo2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-3-methylbenzo[b]thiophene-2-acetamide

To a stirred solution of 0.445 g of 3-methylbenzo[b]thiophene-2-acetylchloride in 5 ml of methylene chloride is added 0.346 g of triethylamineat 0° C. After stirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 72 hours at room temperature. Anadditional 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride, 0.346g of triethylamine and 30 mg of dimethylaminopyridine is added andstirring continued for an additional 18 hours. The reaction mixture isdiluted with 45 ml of methylene chloride and washed with water, 2Ncitric acid, 1M NaCHO₃, and brine. The reaction mixture is dried withNa₂ SO₄, filtered and evaporated in vacuo to give a solid which ispurified by flash chromatography using 1:1 ethyl acetate-hexane to give0.320 g of the desired product as a yellow foam.

EXAMPLE 88 4-Chloro-2-methoxybenzoyl chloride

A solution of 2.0 g of 4-chloro-o-anisic acid in 22 ml of thionylchloride is heated at reflux for 1 hour. The volatiles are evaporated invacuo to give a residue which is is concentrated from toluene threetimes and dried under vacuum to give 2.0 g of the desired product as aresidue.

EXAMPLE 89N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-4-chloro-2-methoxybenzamide

To a stirred solution of 0.406 g of 4-chloro-2-methoxybenzoyl chloridein 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C.After stirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 18 hours at room temperature. Anadditional 0.406 g of 4-chloro-2-methoxybenzoyl chloride and 0.346 g oftriethylamine is added and stirring is continued for 2 hours. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, 1M NaCHO₃, and brine. The reaction mixtureis dried with Na₂ SO₄, filtered and evaporated in vacuo to give aresidue which is purified by flash chromatography using 1:1 ethylacetate-hexane to give a solid which is crystallized from ethyl acetateto give 0.320 g of the desired product as a white crystals., m.p.222°-224° C.

EXAMPLE 90 2-(Trifluoromethyl)benzoyl chloride

A solution of 2.0 g of o-trifluoromethylbenzoic acid in 21 ml of thionylchloride is heated at reflux for 1 hour. The volatiles are evaporated invacuo to give a residue which is concentrated from toluene three timesand dried under vacuum to give 2.1 g of the desired product as aresidue.

EXAMPLE 91N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamide

To a stirred solution of 0.413 g of 2-trifluoromethylbenzoyl chloride in5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C.After stirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 18 hours at room temperature. Thereaction mixture is diluted with 50 ml of ethyl acetate and washed withwater, 2N citric acid, NaHCO3, and brine. The reaction mixture is driedwith Na₂ SO₄, filtered and evaporated in vacuo to give a solid which iscrystallized from ethyl acetate to afford 0.5 g of a solid which isdissolved in methylene chloride and passed through a pad of hydrousmagnesium silicate. The filtrate is evaporated in vacuo to give a solidwhich is crystallized from ethyl acetate to afford 0.210 g of thedesired product as a white crystals, m.p. 226°-228° C.

EXAMPLE 92 2-Methylphenylacetyl chloride

A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chlorideis heated at reflux for 1 hour. The volatiles are evaporated in vacuo togive a residue which is concentrated from toluene three times and driedunder vacuum to give 2.1 g of the desired product as a light brown oil.

EXAMPLE 93N-[4(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-methylbenzeneacetamide

To a stirred solution of 0.334 g of 2-methylphenylacetyl chloride 5 mlof methylene chloride is added 0.346 g of triethylamine at 0° C. Afterstirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis added and stirring continued for 72 hours at room temperature. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, NaCHO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered through a pad of hydrous magnesium silicateand evaporated in vacuo to give a solid which is purified by flashchromatography using 1:1 ethyl acetate-hexane to give a solid which iscrystallized from ethyl acetate to give 0.385 g of the desired productas white crystals, m.p. 198°-200° C.

EXAMPLE 9410,11-Dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 1.81 g of 3-methyl-4-nitrobenzoic acid and 1.25 g ofthionyl chloride in U5 ml of chloroform is heated at reflux under argonfor 48 hours. The volatiles are removed in vacuo to a residue which isevaporated with toluene several times in vacuo. The residue is partiallydissolved in methylene chloride and filtered free of solids and thefiltrate evaporated in vacuo to give 1.47 g of the desired acidchloride. A 1.36 g sample of the acid chloride, 0.90 g ofN,N-diisopropylethylamine and 1.25 g of10,11-di-hydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 25 ml ofmethylene chloride is allowed to stand at room temperature for 8 hours.Water is added to the reaction mixture, the organic layer is separatedand dried over Na₂ SO₄, filtered and hexane added to the filtrate at theboil to give 1.4 g of the desired product as crystals, m.p. 246°-248° C.

EXAMPLE 9510,11-Dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 1.22 g10,11-dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine,0.2 g of 10% Pd/C and 0.35 g of anhydrous hydrazine in 50 ml of absoluteethyl alcohol is heated on a steam bath for 1 hour. The reaction mixtureis filtered hot through diatomaceous earth and evaporated in vacuo to aresidue. The residue is crystallized from methylene chloride-hexane togive 0.95 g of the desired product as crystals, m.p. 232°-234° C.

EXAMPLE 96N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-methylphenyl]-2-methylbenzamide

A solution of 0.83 g of10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine,0.5 g of N,N-diisopropylethylamine and 0.6 g of 2-methylbenzoyl chloridein 50 ml of methylene chloride is stirred at room temperature for 18hours. The reaction mixture is washed with water, the organic layerdried with Na₂ SO₄ and passed through a pad of hydrous magnesiumsilicate. Hexane is added at the boil to give 0.75 g of a solid which iscrystallized from methylene chloride-hexane to give 0.61 g of thedesired product, m.p. 125°-130° C.

                  TABLE IV                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 96 with the                                         appropriately substituted aroyl chloride                                      Example                                                                       No.           Compound                                                        ______________________________________                                         97           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-2-                                                  chlorobenzamide                                                  98           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-2,-                                                 5-dichlorobenzamide                                              99           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2,4-dichlorobenzamide, m.p.                                                   213°-215° C.                                      100           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2-chloro-4-methylbenzamide                                      101           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl)-                                                    2-methyl-4-chlorobenzamide                                      102           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2,3-dimethylbenzamide                                           103           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-2-                                                  methoxybenzamide                                                104           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-2-                                                  trifluoromethoxybenzamide                                       105           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-2,-                                                 4-dimethoxybenzamide                                            106           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    benzamide                                                       107           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2-methylthiobenzamide                                           108           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2,6-dichlorobenzamide                                           109           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2-methyl-3-thiophenecarbox-                                                   amide                                                           110           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2-methyl-3-thiophene-                                                         carboxamide                                                     111           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2-methyl-3-furancarboxamide                                     112           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    3-methyl-2-furancarboxamide                                     113           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    phenylacetamide                                                 114           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2-chlorophenylacetamide                                         115           N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl]-                                                    2-methylphenylacetamide                                         ______________________________________                                    

EXAMPLE 11610,11-Dihydro-10-[4-[[[(2-methylphenyl]amino]-carbonl]amino]benzoyl]-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine

A mixture of 0.93 g10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineand 0.37 g of o-tolyl isocyanate in 50 ml of tetrahydrofuran is heatedat reflux under argon for 24 hours. The volatiles are evaporated invacuo to a residue which is dissolved in methylene chloride and passedthrough a pad of hydrous magnesium silicate. Hexane is added to thefiltrate at the boil to give 0.68 g of the desired product as crystals,m.p. 155°-158° C.

EXAMPLE 117N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-1H-indole-5-carboxamide

To a solution of 319 mg of indole-5-carboxylic acid in 5 ml oftetrahydrofuran is added 418.4 mg of 1,1'-carbonyldiimidazole underargon with ice-bath cooling. The cooling bath is removed and thereaction mixture stirred at room temperature for 2 hours. The volatilesare evaporated in vacuo to a residue which is dissolved in 3 ml ofxylene followed by 500 mg of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c]-[1,4]benzodiazepineand heating at 120° C. for 18 hours. The volatiles are evaporated invacuo to a residue which is partitioned between 40 ml of ethyl acetateand water. The organic layer is dried over Na₂ SO₄ and the volatilesevaporated in vacuo to a residue which is purified by chromatography onpreparative plates by elution with 1:1 ethyl acetate-hexane to give 140mg of the desired product as an orange solid, m.p. 130°-170° C.

EXAMPLE 118 1-(o-Nitrobenzyl)-imidazole-2-carboxaldehyde

A 2.0 g portion of sodium hydride (60% in oil) is washed with pentanetwo times. To the residue is added 110 ml of N,N-dimethylformamide underargon. With stirring and external cooling, 4.80 g of2-imidazolecarboxaldehyde is added and the cooling bath removed. Slightexternal heating results in a yellow solution. The reaction mixture ischilled in ice and 10.8 g of 2-nitrobenzyl bromide is added. Thereaction mixture is stirred at 0° C. for 18 hours. The volatiles areremoved in vacuo to a residue which is stirred with ice water, filteredand the cake washed well with water and suction dried to give 10.9 g ofthe desired product as a solid, m.p. 141°-144° C. MH+232.

EXAMPLE 119 10,11-Dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine

A 5.0 g sample of 1-(o-nitrobenzyl)-imidazole-2-carboxaldehyde isdissolved in 150 ml of hot ethyl alcohol, cooled to room temperature andfiltered. To the filtrate is added 0.5 g of 10% Pd/C and the mixturehydrogenated at 48 psi for 4, hours. An additional 0.5 g of 10% Pd/C isadded and hydrogenation continued for 25 hours at 65 psi. The mixture isfiltered through diatomaceous earth and the cake washed with ethylacetate. The filtrate is evaporated in vacuo to a residue which isdissolved in methylene chloride, treated with activated carbon, filteredthrough diatomaceous earth and hexanes added to the filtrate at the boilto give 1.86 g of the desired product as a crystalline solid, m.p.164°-170° C.

EXAMPLE 120 10,11-Dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine

To a suspension of 4 mmol of lithium aluminum hydride in 20 ml ofanhydrous tetrahydrofuran is added a 1 mmol solution of10,11-dihydro-11-oxo-5H-imidazo[2,1-c][1,4]benzodiazepine and themixture is refluxed for 24 hours and cooled at 0° C. To the mixture isadded dropwise 0.12 ml of water and 6 ml of 1N sodium hydroxide. Themixture is extracted with ethyl acetate and the solvent removed to givethe desired product as a solid. Recrystallization from methylenechloride-hexane gives crystals, m.p. 164°-170° C.

EXAMPLE 121N-[4-(5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoylchloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 mlof triethylamine. After stirring for 3 minutes, 5 mmol of10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylenechloride is added. The cooling bath is removed and after about 30minutes a complete solution is obtained. The reaction mixture is allowedto stir at room temperature for 1 hour and the volatiles areconcentrated in vacuo. The residue is dissolved in 100 ml of ethylacetate and washed with water, 2N citric acid, and brine. The solutionis dried with Na₂ SO₄ and the volatiles concentrated vacuo to give thedesired product as a solid.

EXAMPLE 12210,11-Dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine

To a solution of 10 mmol of10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 50 ml of methylenechloride under argon is added 15 mmol of triethylamine followed by icebath cooling. A solution of 10 mmol of 4-nitrobenzoyl chloride in 10 mlof methylene chloride is added dropwise. Following complete addition,the ice bath is removed and the reaction mixture stirred at roomtemperature for 2 hours. The volatiles are removed in vacuo to give aresidue which is dissolved in ethyl acetate. The solution is washed withwater, and brine. The organic layer is dried with Na₂ SO₄, filtered andevaporated in vacuo to give a solid which is purified by flashchromatography to give desired product as a solid.

EXAMPLE 12310,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine

A mixture of 5 mmol of10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepinein 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of10% Pd/C is hydrogenated for 5 hours in a Parr hydrogenator at 35 psi ofhydrogen. The reaction mixture is filtered through a pad of diatomaceousearth. The filtrate is concentrated in vacuo to a solid which ispurified by flash chromatography to give the desired product.

EXAMPLE 12410,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine

To a solution of 5 mmol of10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepinein 100 ml of ethyl alcohol is added 0.5 g of 10% Pd/C and 10 mmol ofhydrazine followed by stirring and heating under reflux for 3 hours. Thereaction mixture is filtered through diatomaceous earth. The filtrate isconcentrated in vacuo to a residue which is dissolved in methylenechloride and passed through a pad of hydrous magnesium silicate. Thefiltrate is concentrated in vacuo to give the desired product which ispurified by flash chromatography to give the desired product as a solid.

EXAMPLE 125N-[4-(5H-Imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 1.5 mmol of triethylamine. After stirringfor 15 minutes, 1 mmol of10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepineis added and the mixture stirred for 5 hours. The reaction mixture iswashed with water, and brine. The reaction mixture is dried with Na₂SO₄, filtered and evaporated in vacuo to give a solid which is purifiedby flash chromatography to give the desired product as a solid.

                  TABLE V                                                         ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 125 with the                                        appropriately substituted aroyl chloride                                      Example                                                                       No.            Compound                                                       ______________________________________                                        126            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2-                                                         chlorobenzamide                                                127            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,5-                                                       dichlorobenzamide                                              128            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,4-                                                       dichlorobenzamide                                              129            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2-                                                         fluorobenzamide                                                130            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2-chloro-                                                  4-methylbenzamide                                              131            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2-methyl-                                                  4-chlorobenzamide                                              132            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,4-                                                       dimethylbenzamide                                              133            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,3-                                                       dimethylbenzamide                                              134            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2-                                                         methoxybenzamide                                               135            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2-                                                         trifluoromethoxybenzamide                                      136            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,-                                                        4-dimethoxybenzamide                                           137            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,-                                                        6-dimethoxybenzamide                                           138            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-                                                           benzamide                                                      139            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,-                                                        6-dichlorobenzamide                                            140            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,-                                                        6-dimethylbenzamide                                            141            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,-                                                        methylthiobenzamide                                            142            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,-                                                        methyl-3-thiophenecarboxamide                                  143            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-3,-                                                        methyl-2-thiophenecarboxamide                                  144            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-2,-                                                        methyl-3-furanecarboxamide                                     145            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-3,-                                                        methyl-2-furanecarboxamide                                     146            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-                                                           phenylacetamide                                                147            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-                                                           2-chlorophenylacetamide                                        148            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-                                                           2-methylphenylacetamide                                        149            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-                                                           2-methyl-3-thiopheneacetamide                                  150            N-[4-(5H-imidazo[2,1-c][1,4]-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl]-                                                           2-methyl-3-furanacetamide                                      ______________________________________                                    

EXAMPLE 151N-[4-(7-Chloro-5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]phenyl]-2-methylbenzamide

As described for Example 125 a mixture of 1 mmol of7-chloro-10,11-dihydro-5H-imidazo[2,1-c][1,4]-benzodiazepine, 1.1 mmolof 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol oftriethylamine in 10 ml of dichloromethane is stirred at room temperaturefor 3 hours and worked up to give the desired product as a solid.

EXAMPLE 152N-[4-(7-Methoxy-5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]-2-methylbenzamide

As described for Example 125 a mixture of 1.0 mmol of7-methoxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmolof 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol oftriethylamine in 10 ml of dichloromethane is stirred for 3 hours at roomtemperature and worked up to give the product as a solid.

EXAMPLE 153N-[4-(7,8-Methylenedioxy-5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]phenyl]-2-methylbenzamide

As described for Example 125 a mixture of 1.0 mmol of7,8-methylenedioxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine,1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol oftriethylamine in 10 ml of dichloromethane is stirred at room temperaturefor 3 hours and worked up to give the desired product as a solid.

EXAMPLE 154 4,5-Dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline

To a solution of 5 mmol of 4,5-dihydropyrrolo-[1,2-a]quinoxaline in 50ml of methylene chloride under argon is added 10 mmol of triethylaminefollowed by ice bath cooling. A solution of 5 mmol of 4-nitrobenzoylchloride in 10 ml of methylene chloride is added dropwise. Followingcomplete addition, the ice bath is removed and the reaction mixturestirred at room temperature for 2 hours. The volatiles are removed invacuo to give a residue which is dissolved in ethyl acetate. Thesolution is washed with water, 1N HCl, NaHCO₃, and brine. The reactionmixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to givea solid which is purified by flash chromatography to give the desiredproduct (from ethyl acetate) as a solid, m.p. 174°-178° C.

EXAMPLE 155 4,5-Dihydro-5(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline

A mixture of 1 mmol of4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 10 ml ofethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C ishydrogenated for 5 hours. The reaction mixture is filtered through a padof diatomaceous earth. The filtrate is concentrated in vacuo to a solidwhich is purified by flash chromatography to give the desired product,m.p. 225°-228° C.

EXAMPLE 156 4,5-Dihydro-5(4-aminobenzoyl)pyrrolo[1,2-a]qinoxaline

To a solution of 1 mmol of4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 20 ml ofethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazinefollowed by stirring and heating under reflux for 2 hours. The hotreaction mixture is filtered through diatomaceous earth and the filtercake washed with hot chloroform and the filtrate concentrated in vacuo.The residue is triturated with ethyl acetate and the mixture filtered togive the desired product as crystals, m.p. 225°-228° C.

EXAMPLE 157N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 1.5 mmol of 2-methylbenzoyl chloride in 10 mlof methylene chloride is added 3 mmol of triethylamine. After stirringfor 15 minutes, 1.5 mmol of4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline is added and themixture stirred for 5 hours. The reaction mixture is washed with water,1N HCl, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄,filtered and evaporated in vacuo to give a solid which is purified byflash chromatography to give the desired product as a solid, m.p.206°-207° C.

                  TABLE VI                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 157 with the                                        appropriately substituted aroyl chloride                                      Example                                                                       No.         Compound                                                          ______________________________________                                        158         N-[4-(pyrrolo[1,2-a]quinoxalin-                                               5(4H)ylcarbonyl)phenyl]-2-                                                    chlorobenzamide                                                   159         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl]phenyl-2,5-dichloro-                                               benzamide                                                         160         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,4-dichloro-                                              benzamide, m.p. 200°-202° C.                        161         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-chloro-4-methyl-                                         benzamide                                                         162         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methyl-4-chloro-                                         benzamide                                                         163         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,4-dimethyl-                                              benzamide                                                         164         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,3-dimethyl-                                              benzamide, m.p. 216°-220° C.                        165         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methoxy-                                                 benzamide                                                         166         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-trifluoro-                                               methoxybenzamide                                                  167         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,4-dimethoxy-                                             benzamide                                                         168         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,6-dimethoxy-                                             benzamide                                                         169         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]benzamide                                       170         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,6-dichloro-                                              benzamide                                                         171         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2,6-dimethyl-                                              benzamide                                                         172         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-(methylthio)-                                            benzamide                                                         173         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methyl-3-                                                thiophenecarboxamide                                              174         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-3-methyl-2-                                                thiophenecarboxamide                                              175         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methyl-3-                                                furanecarboxamide                                                 176         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-3-methyl-2-                                                furanecarboxamide                                                 177         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]benzeneacetamide                                178         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-chlorobenzene                                            acetamide                                                         179         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methylbenzene                                            acetamide, yellow foam                                            180         N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                         ylcarbonyl)phenyl]-2-methyl-3-                                                thiopheneacetamide                                                ______________________________________                                    

EXAMPLE 181 9,10-Dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine

To a suspension of 4 mmol of lithium aluminum hydride in 25 ml ofanhydrous tetrahydrofuran is added 1 mmol of9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-9-one. Themixture is refluxed for 12 hours and allowed to stand overnight. To themixture is added dropwise 0.12 ml of water and then 6 ml of 1N sodiumhydroxide. The mixture is extracted with ethyl acetate and the extractdried(Na₂ SO₄). The volatiles are removed in vacuo to give the desiredproduct as a solid.

EXAMPLE 182 9,10-Dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine

A solution of 1 mmol of 4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine and0.2 g of 10% Pd/C in 10 ml of 10 ml of ethanol is hydrogenated for 18hours. The reaction mixture is filtered through diatomaceous earth andthe filtrate is evaporated in vacuo to give the desired product as asolid.

EXAMPLE 183N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10-(9H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloridein 10 ml of methylene chloride, cooled to 0° C. is added 1.5 mmol oftriethylamine. To the mixture is added 1 mmol of9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine and the mixturestirred at room temperature for 2 hours. The reaction mixture isconcentrated in vacuo and the residue is dissolved in 100 ml of ethylacetate and washed with water, 2N citric acid, aqueous NaHCO₃ and brine.The solution is dried with Na₂ SO₄ and the volatiles concentrated invacuo to give a solid which is purified by flash chromatography to givethe desired product.

EXAMPLE 1849,10-Dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine

To a solution of 1.0 mmol of9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml ofmethylene chloride under argon is added 1.5 mmol of triethylaminefollowed by ice bath cooling. A solution of 1.1 mmol of 4-nitrobenzoylchloride in 5 ml of methylene chloride is added dropwise. Followingcomplete addition, the ice bath is removed and the reaction mixture isstirred at room temperature for 2 hours. The volatiles are removed invacuo to give a residue which is dissolved in ethyl acetate. Thesolution is washed with water, 1N HCl, NaCHO₃, and brine. The reactionmixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to givea solid which is purified by flash chromatography on silica gel to givedesired product as a solid.

EXAMPLE 1859,10-Dihydro-10-(4-aminobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine

A mixture of 1 mmol of9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepinein 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filteredthrough a pad of diatomaceous earth. The filtrate is concentrated invacuo to a solid which is purified by flash chromatography on silica gelto give the desired product.

EXAMPLE 1869,10-Dihydro-10-(4-aminobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine

To a solution of 1 mmol of9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepinein 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol ofhydrazine followed by stirring and heating under reflux for 3 hours. Theroom temperature reaction mixture is filtered through diatomaceous earthand the filtrate concentrated in vacuo. The residue is dissolved inmethylene chloride and passed through a thin pad of hydrous magnesiumsilicate. The filtrate is concentrated in vacuo to give the desiredproduct which is purified by flash chromatography on silica gel to givethe desired product as a solid.

EXAMPLE 187N-[4-(4H-Furo[2,3e]pyrrolo[1,2-a][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 1.5 mmol of triethylamine. To the mixture isadded 1.1 mmol of9,10-dihydro-10-(4-aminobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepineand the mixture is stirred for 5 hours. The reaction mixture is washedwith water, 1N citric acid, NaHCO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography on silica gel with ethylacetate-hexane as solvent to give the desired product as a solid.

                  TABLE VII                                                       ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 187 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.         Compound                                                          ______________________________________                                        188         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-chlorobenzamide                                         189         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2,5-dichlorobenzamide                                     190         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2,4-dichlorobenzamide                                     191         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-chloro-4-methylbenzamide                                192         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-methyl-4-chlorobenzamide                                193         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2,4-dimethylbenzamide                                     194         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2,3-dimethylbenzamide                                     195         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-methoxybenzamide                                        196         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-trifluoromethoxybenzamide                               197         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2,4-dimethoxybenzamide                                    198         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-methoxy-4-chlorobenzamide                               199         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2,6-dichlorobenzamide                                     200         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-methylthiobenzamide                                     201         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-methyl-3-thiophene-                                                 carboxamide                                                       202         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-3-methyl-2-thiophene-                                                 carboxamide                                                       203         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-methyl-3-furane-                                                    carboxamide                                                       204         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-3-methyl-2-furane-                                                    carboxamide                                                       205         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-chlorobenzeneacetamide                                  206         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-methylbenzeneacetamide                                  207         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-2-methyl-3-thiophene-                                                 acetamide                                                         208         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-cyclohexanecarboxamide                                    209         N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                           [1,4]diazepin-10(9H)-ylcarbonyl)-                                             phenyl]-cyclohexylacetamide                                       ______________________________________                                    

EXAMPLE 210N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 1.37 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml oftriethylamine. To the mixture is added 5 mmol of5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine. The reaction mixtureis allowed to stir at room temperature for 48 hours and the volatilesare removed in vacuo to give a residue. The residue is dissolved in 100ml of ethyl acetate and washed with water, 2N citric acid, aqueousNaHCO₃ and brine. The solution is dried with Na₂ SO₄ and the solventremoved in vacuo. The residue is purified by flash chromatography onsilica gel with ethyl acetate-hexane to give the desired product, m.p.142°-146° C.

EXAMPLE 2115,10-Dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine

To a solution of 10 mmol of5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylenechloride under argon is added 15 mmol of triethylamine followed by icebath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 mlof methylene chloride is added dropwise. Following complete addition,the ice bath is removed and the reaction mixture stirred at roomtemperature for 2 hours. The volatiles are removed in vacuo to give aresidue which is dissolved in ethyl acetate. The solution is washed withwater, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄,filtered and evaporated in vacuo to give a solid which is purified byflash chromatography on silica gel to give desired product as a solid,m.p. 227°-229° C.

EXAMPLE 2125,10-Dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine

A mixture of 5 mmol of5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepinein 25 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filteredthrough a pad of diatomaceous earth. The filtrate is concentrated invacuo to a solid which is purified by flash chromatography on silica gelto give the desired product as a tan solid.

EXAMPLE 2135,10-Dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine

To a solution of 5 mmol of5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepinein 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol ofhydrazine. The :mixture is heated under reflux for 3 hours, and themixture is filtered through diatomaceous earth. The filtrate isconcentrated in vacuo to a residue which is dissolved in methylenechloride and passed through a thin pad of hydrous magnesium silicate.The filtrate is concentrated in vacuo to give the desired product whichis purified by flash chromatography on silica gel to give the desiredproduct as a solid, exact mass by mass spectrometry: 305.1402(M+H).

EXAMPLE 214N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 5 mmol of triethylamine and 3 mmol of5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine.The mixture is stirred at room temperature for 5 hours and is thenwashed with water, NaHCO₃, and brine. The organic layer is dried withNa₂ SO₄, filtered and evaporated in vacuo to give a solid which ispurified by flash chromatography on silica gel to give the desiredproduct as a solid, m.p. 142°-146° C.

                  TABLE VIII                                                      ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 214 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.         Compound                                                          ______________________________________                                        215         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-methoxybenzeneacetamide, m.p.                                               185-188° C.                                                216         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2,5-dichlorobenzamide                                             217         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2,4-dichlorobenzamide, colorless                                              foam; exact mass by mass spectro-                                             metry: 479.0896 (M+H)                                             218         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-chloro-4-methylbenzamide                                        219         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-methyl-4-chlorobenzamide                                        220         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2,4-dimethylbenzamide                                             221         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2,3-dimethylbenzamide                                             222         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-methoxybenzamide                                                223         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-trifluoromethoxybenzamide                                       224         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2,4-dimethoxybenzamide                                            225         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2,6-dimethoxybenzamide                                            226         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           benzamide                                                         227         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2,6-dichlorobenzamide                                             228         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2,6-dimethylbenzamide                                             229         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-methylthiobenzamide                                             230         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-methyl-3-thiophenecarboxamide                                   231         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           3-methyl-2-thiophenecarboxamide                                   232         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-methyl-3-furanecarboxamide                                      233         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           3-methyl-2-furanecarboxamide                                      234         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           3-cyclohexenecarboxamide                                          235         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-chlorobenzeneacetamide                                          236         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-methylbenzeneacetamide                                          237         N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl]-                                           2-methyl-3-thiopheneacetamide                                     ______________________________________                                    

EXAMPLE 238 9,10-Dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine

To a mixture of 7.0 g of9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin in 25 mlof anhydrous tetrahydrofuran is added 9 ml of 10 molarboron-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6hours. The solution is cooled to room temperature and 25 ml of methanoladded dropwise. The volatiles are removed under vacuum. To the residueis added 100 ml of 2N NaOH. The mixture is refluxed 5 hours andfiltered. The solid is extracted with dichloromethane and the extract iswashed with 2N citric acid, water and dried (Na₂ SO₄). The solvent isremoved in vacuo to give the desired product as a solid.

EXAMPLE 239N-[4-(4H-Pyrazolo[1,2-a]thieno[2,3-a][1,4]-diazepin-10(9H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 1.37 g (5mmol) of 4-[(2-methylbenzoyl)amino]benzoylchloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 mlof triethylamine. To the mixture is added 5 mmol of9,10-dihydro-4H-pyrazolo[1,2-a]thieno[2,3-e][1,4]diazepine. The coolingbath is removed and the reaction mixture is allowed to stir at roomtemperature for 48 hours. The volatiles are removed in vacuo to give aresidue. The residue is dissolved in 100 ml of ethyl acetate and washedwith water, 2N citric acid, aqueous NaHCO₃ and brine. The solution isdried with Na₂ SO₄ and the solvent removed in vacuo to) give a solid.The solid is purified by flash chromatography on silica gel to give thedesired product.

EXAMPLE 2409,10-Dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine

To a solution of 10 mmol of9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine in 50 ml ofmethylene chloride under argon is added 15 mmol of triethylaminefollowed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoylchloride in 10 ml of methylene chloride is added dropwise. Followingcomplete addition, the ice bat]h is removed and the reaction mixturestirred at room temperature for 2 hours. The volatiles are removed invacuo to give a residue which is dissolved in ethyl acetate. Thesolution is washed with water, 1N HCl, NaCHO₃, and brine. The organiclayer is dried with Na₂ SO₄, filtered and evaporated in vacuo to give asolid which is purified by flash chromatography on silica gel to givedesired product as a solid.

EXAMPLE 2419,10-Dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]diazepine

A mixture of 2 g of9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]diazepinein 20 ml of ethyl alcohol and 20 ml of ethyl acetate containing 0.2 g of10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filteredthrough a pad of diatomaceous earth. The filtrate is concentrated invacuo to a solid which is purified by flash chromatography to give thedesired product.

EXAMPLE 2429,10,Dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]diazepine

To a solution of 5 mmol of9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]diazepinein 25 ml of ethyl alcohol is added 0.13 g of 1.0% Pd/C and 15 mmol ofhydrazine followed by stirring and heating under reflux for 3 hours. Thecooled reaction mixture is filtered through diatomaceous earth. Thefiltrate is concentrated in vacuo to a residue which is dissolved inmethylene chloride and passed through a pad of hydrous magnesiumsilicate. The filtrate is concentrated in vacuo to give the desiredproduct which is purified by flash chromatography on silica gel to givethe desired product as a solid.

EXAMPLE 243N-[4-(4H-Pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(9H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 7 mmol of triethylamine and 5 mmol of9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e]-[1,4]diazepineand the mixture stirred for 5 hours. The reaction mixture is washed withwater, 2N citric acid, NaCHO₃, and brine. The organic layer is driedwith Na₂ SO₄, filtered and evaporated in vacuo to give a solid which ispurified by flash chromatography on silica gel to give the desiredproduct as a solid.

                  TABLE IX                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 243 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.         Compound                                                          ______________________________________                                        244         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-chloro-                                                    benzamide                                                         245         N-(4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2,5-dichloro-                                                benzamide                                                         246         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2,4-dichloro-                                                benzamide                                                         247         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-chloro-                                                    4-methylbenzamide                                                 248         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-methyl-                                                    4-chlorobenzamide                                                 249         N-(4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2,4-                                                         dimethylbenzamide                                                 250         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2,3-                                                         dimethylbenzamide                                                 251         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-methoxy-                                                   benzamide                                                         252         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-                                                           trifluoromethoxybenzamide                                         253         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2,4-                                                         dimethoxybenzamide                                                254         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2,6-                                                         dimethoxybenzamide                                                255         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2,6-                                                         dichlorobenzamide                                                 256         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2,6-                                                         dimethylbenzamide                                                 257         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-                                                           methoxy-4-chlorobenzamide                                         258         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-                                                           methoxybenzeneacetamide                                           259         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-(methylthio)-                                              benzamide                                                         260         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-                                                           methyl-3-thiophenecarboxamide                                     261         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-3-methyl-2-                                                  thiophenecarboxamide                                              262         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-3-methyl-2-                                                  furancarboxamide                                                  263         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-3-                                                           chlorophenylacetamide                                             264         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-                                                           methylbenzeneacetamide                                            265         N-[4-(4H-pyrrolo[1,2-a]thieno-                                                [2,3-e][1,4]diazepin-10(9H)-yl                                                carbonyl)phenyl]-2-                                                           methyl-3-thiopheneacetamide                                       ______________________________________                                    

EXAMPLE 266 4,10-Dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine

To a suspension of 7.0 g of5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 25 ml ofanhydrous tetrahydrofuran is added 9 ml of 10M borane-dimethylsulfide intetrahydrofuran. The mixture is refluxed for 6 hours. The solution iscooled to room temperature and 25 ml of methanol added dropwise. Thevolatiles are removed under vacuum. To the residue is added 100 ml of 2NNaOH. The mixture is refluxed 5 hours and filtered. The solid isextracted with dichloromethane and the extract is washed with 2N citricacid, water and dried (Na₂ SO₄). The solvent is removed to give a solid.

EXAMPLE 267N-[4-(5H-Pyrazolo[1,2-a]thieno[3,2-e][1,4]-diazepin-4(10H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloridein 20 ml of methylene chloride, cooled to 0° C. is added 7.5 mmol oftriethylamine and 5 mmol of4,10-dihydro-5H-pyrazolo[1,2-a]thieno[3,2-e][1,4]diazepine. The coolingbath is removed and the reaction mixture is allowed to stir at roomtemperature for 48 hours. The volatiles are removed in vacuo to give aresidue. The residue is dissolved in 100 ml of ethyl acetate and thesolution washed with water, 2N citric acid, aqueous NaHCO₃ and brine.The solution is dried with Na₂ SO₄ and the solvent concentrated in vacuoto give a solid. The solid is purified by flash chromatography on silicagel to give the desired product as a solid and foam, m.p. 162°-188° C.,Anal. Calc'd for C₂₅ H₂₁ N₃ O₂ S: C,70.2; H,5.0 N,9.8; S,7.5 Found:C,69.5, H,5.2 N,9.6; S,7.0.

EXAMPLE 2684,10-Dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin

To a solution of 3 mmol of4,10-dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 10 ml ofmethylene chloride under argon is added 5 mmol of triethylamine followedby ice bath cooling. A solution of 3.3 mmol of 4-nitrobenzoyl chloridein 3 ml of methylene chloride is added dropwise. Following completeaddition, the ice bath is removed and the reaction mixture stirred atroom temperature for 2 hours. The volatiles are removed in vacuo to givea residue which is dissolved in ethyl acetate. The solution is washedwith water, 2N citric acid, NaCHO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography on silica gel to give desiredproduct as a solid.

EXAMPLE 2694,10-Dihydro-4-(4-aminobenzoyl-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine

A mixture of 5 mmol of4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]-diazepinein 25 ml of ethyl alcohol and 25 ml of ethyl acetate containing 0.2 g of10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filteredthrough a pad of diatomaceous earth. The filtrate is concentrated invacuo to a solid which is purified by flash chromatography on silica gelto give the desired product.

EXAMPLE 2704,10-Dihydro-4-(4-aminobenzoyl)-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine

To a mixture of 5 mmolof4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepinein 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol ofhydrazine followed by stirring and heating under reflux for 3 hours. Thecooled reaction mixture is filtered through diatomaceous earth. Thefiltrate is concentrated in vacuo to a residue which is dissolved inmethylene chloride and passed through a pad of hydrous magnesiumsilicate. The filtrate is concentrated in vacuo to give the desiredproduct which is purified by flash chromatography on silica gel to givethe desired product as a solid.

EXAMPLE 271N-[4-(5H-Pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-4(10H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 5 mmol of triethylamine and 3 mmol of4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e]-[1,4]diazepine.The mixture is stirred for 5 hours. The reaction mixture is washed withwater, 2N citric acid, NaHCO₃, and brine. The reaction mixture is driedwith Na₂ SO₄, filtered and evaporated in vacuo to give a solid which ispurified by flash chromatography on silica gel to give the desiredproduct as a solid, m.p. 162°-188° C. (amorphous)

                  TABLE X                                                         ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 271 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.         Compound                                                          ______________________________________                                        272         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-chloro-                                                    benzamide                                                         273         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2,5-dichloro-                                                benzamide                                                         274         N-(4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2,4-dichloro-                                                benzamide (solid foam), m.p. 105-                                             190° C.; Anal Calc'd for C.sub.24 H.sub.17 N.sub.3                     Cl.sub.2 O.sub.2 S: C, 59.8; H, 3.6; N, 8.7;                                  S, 6.6, Cl, 14.7 Found: C, 59.6;                                              H, 3.8; N, 8.1; S, 5.5; Cl, 14.0                                  275         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-chloro-                                                    4-methylbenzamide                                                 276         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-methyl-                                                    4-chlorobenzamide                                                 277         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2,4-dimethyl-                                                benzamide                                                         278         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2,3-dimethyl-                                                benzamide                                                         279         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-methoxy-                                                   benzamide                                                         280         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-trifluoro-                                                 methoxybenzamide                                                  281         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2,4-                                                         dimethoxybenzamide                                                282         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2,6-                                                         dimethoxybenzamide                                                283         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2,6-                                                         dichlorobenzamide                                                 284         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2,6-                                                         dimethylbenzamide                                                 285         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-methylthio-                                                benzamide                                                         286         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-                                                           methyl-3-thiophenecarboxamide                                     287         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-3-                                                           methyl-2-thiophenecarboxamide                                     288         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-3-                                                           methyl-2-furancarboxamide                                         289         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-3-chloro-                                                    benzeneacetamide                                                  290         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-methoxy-                                                   benzeneacetamide                                                  291         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-methoxy-4-                                                 chlorobenzamide                                                   292         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-methylbenzene-                                             acetamide                                                         293         N-[4-(5H-pyrrolo[1,2-a]thieno-                                                [3,2-e][1,4]diazepin-4(10H)-yl                                                carbonyl)phenyl]-2-                                                           methyl-3-thiopheneacetamide                                       ______________________________________                                    

EXAMPLE 2946,7-Dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a]-[1,5]benzodiazepine

To a solution of 10 mmol of6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 30 ml of methylenechloride under argon is added 15 mmol of triethylamine followed by icebath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 mlof methylene chloride is added dropwise. Following complete addition,the ice bath is removed and the reaction mixture stirred at roomtemperature for 2 hours. The volatiles are removed in vacuo to give aresidue which is dissolved in ethyl acetate. The solution is washed withwater, 2N citric acid, NaHCO₃, and brine. The reaction mixture is driedwith Na₂ SO₄, filtered and evaporated in vacuo to give a solid which ispurified by flash chromatography on silica gel to give the desiredproduct as a solid.

EXAMPLE 2956,7-Dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2a][1,5]benzodiazepine

A mixture of 2.0 g of6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine, 20ml of ethyl alcohol and 20 ml of ethyl acetate containing 0.2 g of 10%Pd/C is hydrogenated for 5 hours. The reaction mixture is filteredthrough a pad of diatomaceous earth. The filtrate is concentrated invacuo to a solid which is purified by flash chromatography on silica gelto give the desired product.

EXAMPLE 2966,7-Dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2a]-[1,5]benzodiazepine

To a solution of 5 mmol of6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine in25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol ofhydrazine followed by stirring and heating under reflux for 3 hours. Thereaction mixture is filtered through diatomaceous earth. The filtrate isconcentrated in vacuo to a residue which is dissolved in methylenechloride and passed through a pad of hydrous magnesium silicate. Thefiltrate is concentrated in vacuo to give the desired product which ispurified by flash chromatography on silica gel to give the desiredproduct as a solid.

EXAMPLE 297N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-ylcarbonyl]phenyl]-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoylchloride in 10 ml of methylene chloride, cooled to 0° C. is added 7 mmolof triethylamine and 5 mmol of6,7-dihydro-5H-pyrrolo-[1,2-a][1,5]benzodiazepine. The cooling bath isremoved and the reaction mixture is allowed to stir at room temperaturefor 48 hours. The volatiles are removed in vacuo to give a residue. Theresidue is dissolved in 100 ml of ethyl acetate and washed with water,2N citric acid, aqueous NaHCO₃ and brine. The solution is dried with Na₂SO₄ and the solvent removed in vacuo to give a solid. The solid istriturated with ether-hexane to give the desired product, mass spectrum(CI): 422 (M+H).

EXAMPLE 298N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-ylcarbonyl)phenyl]-2-methyl-benzamide

To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 7 mmol of triethylamine and 5 mmol of6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a]-[1,5]benzodiazepine.The reaction mixture is washed with water, 2M citric acid, NaHCO₃, andbrine. The organic layer is dried with Na₂ SO₄, filtered and evaporatedin vacuo to give a solid which is purified by flash chromatography onsilica gel to give the desired product as a solid; mass spectrum (CI):422 (M+H).

                  TABLE XI                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 298 with the                                        appropriately substituted aroyl                                               chloride.                                                                     Example                                                                       No.         Compound                                                          ______________________________________                                        299         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-                                                           chlorobenzamide                                                   300         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2,5-di-                                                      chlorobenzamide                                                   301         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2,4-di-                                                      chlorobenzamide                                                   302         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-                                                           chloro-4-methylbenzamide                                          303         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-                                                           methyl-4-chlorobenzamide                                          304         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2,4-                                                         dimethylbenzamide                                                 305         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2,3-                                                         dimethylbenzamide                                                 306         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-                                                           methoxybenzamide                                                  307         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-                                                           trifluoromethoxybenzamide                                         308         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2,4-                                                         dimethoxybenzamide                                                309         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2,6-                                                         dimethoxybenzamide                                                310         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2,6-                                                         dichlorobenzamide                                                 311         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2,6-                                                         dimethylbenzamide                                                 312         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-                                                           methylthiobenzamide                                               313         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-                                                           methyl-3-thiophenecarboxamide                                     314         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-3-                                                           methyl-2-thiophenecarboxamide                                     315         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-                                                           methyl-3-furanecarboxamide                                        316         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-3-methyl-2-                                                  furanecarboxamide                                                 317         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]benzeneacetamide                                  318         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-chlorobenzene-                                             acetamide                                                         319         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-methylbenzene-                                             acetamide                                                         320         N-[4-[(6,7-dihydro-5H-pyrrolo                                                 [1,2-a][1,5]benzodiazepin-5-yl)                                               carbonyl]phenyl]-2-methyl-3-                                                  thiopheneacetamide                                                ______________________________________                                    

EXAMPLE 321 5,6-Dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine

A mixture of 7.0 g of5,6-dihydro-4H-[1,2,4]-triazolo-[4,3-a][1,5]benzodiazepin-5-one in 25 mlof tetrahydrofuran is added 9 ml of 10M borane-dimethylsulfide intetrahydrofuran. The mixture is refluxed for 6 hours, cooled to roomtemperature and 25 ml of methanol added dropwise. The volatiles areremoved under vacuum and to the residue is added 100 ml of 2N sodiumhydroxide. The mixture is refluxed for 5 hours, chilled and extractedwith dichloromethane. The extract is washed with 2N citric acid, waterand dried (Na₂ SO₄). The solvent is removed under vacuum to give asolid. The solid is purified by chromatography on silica gel to give thedesired product.

EXAMPLE 322N-[4(4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6(5H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 5 mmol of5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml ofdichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoylchloride and then 7.5 mmol of triethylamine. The mixture is stirred atroom temperature for 8 hours and then washed with water, aqueous NaHCO₃and brine. The solution is dried (Na₂ SO₄) and the solvent removed invacuo to give a solid. The solid is purified by chromatography on silicagel with ethyl acetate-hexane as solvent to give the desired product asa glass.

EXAMPLE 3235,6-Dihydro-6-(4-nitrobenzoyl)-4H-[1,2,4]triazolo-[4,3-a][1,5]benzodiazepin

To a mixture of 3 mmol of5,6-dihydro-4H-[1,2,4]-triazolo[4,3-a][1,5]benzodiazepine in 10 ml ofdichloromethane under argon is added 5 mmol of triethylamine. To themixture is added dropwise 3.3 mmol of 4-nitrobenzoyl chloride in 3 ml ofdichloromethane. The mixture is stirred at room temperature 3 hours andthen washed with water, aqueous NaHCO₃ and brine. The organic layer isdried (Na₂ SO₄) and the solvent removed under vacuum. The residue ispurified by chromatography on silica gel to give the desired product asa solid.

EXAMPLE 3245,6-Dihydro-6-(aminobenzoyl)-4H-[1,2,4]triazolo-[4,3-a][1,4]benzodiazepine

To a mixture of 5 mmol of5,6-dihydro-6-(4-nitrobenzoyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepinein 25 ml of ethanol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine.The mixture is refluxed for 3 hours, cooled and filtered throughdiatomaceous earth. The filtrate is concentrated in vacuo and theresidue purified by chromatography on silica gel to give the desiredproduct as a solid.

                  TABLE XII                                                       ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 322 with the                                        appropriately substituted aroyl                                               chloride                                                                      Example                                                                       No.         Compound                                                          ______________________________________                                        325         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-chlorobenzamide                                                 326         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,5-dichlorobenzamide                                             327         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,4-dichlorobenzamide                                             328         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,3-difluorobenzamide                                             329         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-chloro-4-methylbenzamide                                        330         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methyl-4-chlorobenzamide                                        331         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,4-dimethylbenzamide                                             332         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,3-dimethylbenzamide                                             333         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methoxybenzamide                                                334         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-trifluoromethoxybenzamide                                       335         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,3-dichlorobenzamide                                             336         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,4-dimethoxybenzamide                                            337         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,6-dimethoxybenzamide                                            338         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methoxy-4-chlorobenzamide                                       339         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-trifluoromethylbenzamide                                        340         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,6-dichlorobenzamide                                             341         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2,6-dimethylbenzamide                                             342         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methylthiobenzamide                                             343         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methyl-3-thiophenecarboxamide                                   344         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        3-methyl-2-thiophenecarboxamide                                   345         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methyl-3-furanecarboxamide                                      346         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methyl-3-furanecarboxamide                                      347         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        3-methyl-2-furanecarboxamide                                      348         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methoxybenzeneacetamide                                         349         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methylbenzeneacetamide                                          350         N-[4-(4H-(1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-chlorobenzeneacetamide                                          351         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                        2-methyl-3-thiopheneacetamide                                     ______________________________________                                    

EXAMPLE 352N-[4-(1-Methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6(5H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 5 mmol of5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20ml of dichloromethane is added 5.5 mmol of4-[(2-methylbenzoyl)amino]benzoyl chloride and 7.5 mmol oftriethylamine. The mixture is stirred at room temperature for 8 hoursand then washed with water, aqueous NaHCO₃ and brine. The organic layeris dried (Na₂ SO₄) and the solvent removed in vacuo to give a solid. Thesolid is purified by chromatography on silica gel with ethylacetate-hexane as solvent to give the desired product.

EXAMPLE 353N-[4-(1-Methyl-4H-[1,2,4triazolo[4,3,-a][1,5]benzodiazepin-6(5H)-ylcarbonyl)phenyl]-2,4dichlorobenzamide

To a mixture of 5 mmol of5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20ml of dichloromethane is added 5.5 mmol of4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride and 7.5 mmol oftriethylamine. The mixture is stirred at room temperature for 8 hoursand then washed with water, aqueous NaHCO₃ and brine. The organic layeris dried (Na₂ SO₄) and the solvent removed in vacuo to give a solid. Thesolid is purified by chromatography on silica gel to give the desiredproduct as a solid.

EXAMPLE 354N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11)-ylcarbonyl)phenyl]-3-cyclohexenecarboxamide

A mixture of 0.50 g of10,11-dihydro-10(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine,0.286 g of 3-cyclohexenecarbonyl chloride and 346 μl of triethylamine in5 ml of dichloromethane is stirred at room temperature 16 hours. Themixture is diluted with 50 ml of dichloromethane and the solution washedwith 20 ml of water, 2N citric acid, 1N NaHCO₃, brine and dried (Na₂SO₄). The solution is filtered through a thin pad of hydrous magnesiumsilicate and the filtrate evaporated in vacuo. The residue ischromatographed on thick layer silica gel plates to give a solid whichis crystallized from ethyl acetate to give 0.34 g of crystals, m.p.216°-218° C.

EXAMPLE 355N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11)ylcarbonyl)phenyl]-5-methyl-2-thiophenecarboxamide

To a solution of 0.318 g of 5-methyl-2-thiophenecarbonyl chloride in 5ml of dichloromethane cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepineand 346 μl of triethylamine. The mixture is stirred at room temperature16 hours and diluted with 50 ml of dichloromethane. The solution iswashed with 20 ml each of water, 2N citric acid. 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filtrate evaporated in vacuo to give a solid.The solid is crystallized from ethyl acetate to give 0.53 g of crystals,m.p. 235°-238° C.

EXAMPLE 356N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11)ylcarbonyl)phenyl]-cyclohexylacetamide

To a solution of 0.318 g of cyclohexylacetyl chloride in 5 ml ofdichloromethane cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepineand 346 μl of triethylamine. The mixture is stirred at room temperature16 hours and diluted with 50 ml of dichloromethane. The solution iswashed with 20 ml each of water, 2N citric acid. 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filtrate evaporated in vacuo to give a solid.The solid is crystallized from ethyl acetate to give 0.52 g of crystals,m.p. 231°-234° C.

EXAMPLE 357N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11)ylcarbonyl)phenyl]-2-fluorobenzeneacetamide

To a solution of 0.342 g of 2-fluorophenylacetyl chloride in 5 ml ofdichloromethane cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepineand 346 μl of triethylamine. The mixture is stirred at room temperature16 hours and diluted with 50 ml of dichloromethane. The solution iswashed with 20 ml each of water, 2N citric acid. 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filtrate evaporated in vacuo to give a solid.The solid is crystallized from ethyl acetate to give 0.43 g of crystals,m.p. 204°-207° C.

EXAMPLE 358N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11)ylcarbonyl)phenyl]-cyclohexanecarboxamide

To a solution of 0.342 g of cyclohexanecarbonyl chloride in 5 ml ofdichloromethane cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiaiepineand 346 μl of triethylamine. The mixture is stirred at room temperature16 hours and diluted with 50 ml of dichloromethane. The solution iswashed with 20 ml each of water, 2N citric acid. 1M NaCHO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filtrate evaporated in vacuo to give a solid.The solid is crystallized from ethyl acetate to give 0.54 g of crystals,m.p. 202°-204° C.

EXAMPLE 359 4-[N-Methyl-N-(2-methylbenzoylamino]benzoyl chloride

A solution of 6.72 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoicacid in 20 ml of thionyl chloride is refluxed for one hour. Thevolatiles are removed in vacuo. Toluene is added to the residue and thenthe toluene removed in vacuo (repeated several times) to give the 7.3 gof product as a brown oil.

EXAMPLE 360 4-[N-Methyl-N-(2-methylbenzoyl)amino]benzoic acid

A sample of 1.51 g of sodium hydride (60% in oil) is washed with hexaneunder argon to remove the oil. To the washed sodium hydride is added 5ml of N,N-dimethylformamide. To this mixture is added dropwise asolution of 8.69 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate in 20 mlof N,N-dimethylformamide. The mixture is stirred at room temperature for0.5 hour and then 5.23 g of methyl iodide is added. The mixture isstirred at room temperature for 16 hours. The mixture is diluted withwater and extracted with dichloromethane. The extract is dried (Na₂SO₄), concentrated to reduce the volume and the solution filteredthrough a thin pad of hydrous magnesium silicate. The filtrate isconcentrated vacuo to give 11 g of an oil (1:1 mixture of product andN,N-dimethylformamide). The preceding product, ethyl4-[N-methyl-N-(2-methylbenzoyl)amino]benzoate, (11 g) is dissolved in 30ml of methanol and 25 ml of 2N NaOH added. The mixture is refluxed for 2hours and the solvent removed. The residue is extracted with ether(discard) and the remaining residue dissolved in 50 ml of water. Thebasic solution is acidified with 2N citric acid and the solid filteredoff and washed with water. The product is air dried to give 6.72 g ofcrystals, m.p. 187°-190° C.

As described for Example 360 but substituting the appropriate ethyl4-[(N-aroyl)amino]benzoate, the following compounds are prepared.

EXAMPLE 361 4-[N-Methyl-N-(2-chlorobenzoyl) amino]benzoic acid EXAMPLE362 4-[N-Methyl -N-(2,5-dichlorobenzoyl)amino]benzoic acid EXAMPLE 3634-[N-Methyl-N-(2,4-dichlorobenzoyl)amino]benzoic acid EXAMPLE 3644-[N-Methyl-N-(2-chloro-4-methylbenzoyl)amino]benzoic acid EXAMPLE 3654-[N-Methyl-N-(2-methyl-4-chlorobenzoyl)amino]benzoic acid EXAMPLE 3664-[N-Methyl-N-(2,4-dimethylbenzoyl)amino]benzoic acid EXAMPLE 3674-[N-Methyl-N-(2,3-dimethylbenzoyl)amino]benzoic acid EXAMPLE 3684-[N-Methyl-N-(2-methoxybenzoyl)amino]benzoic acid EXAMPLE 3694-[N-Methyl-N-(2-trifluoromethoxybenzoyl)amino]benzoic acid EXAMPLE 3704-[N-Methyl-N-(2,4-dimethoxybenzoyl)amino]benzoic acid EXAMPLE 3714-[N-Methyl-N-(2-methoxy-4-chlorobenzoyl)amino]benzoic acid EXAMPLE 3724-[N-Methyl-N-(2-methylthiobenzoyl)amino]benzoic acid EXAMPLE 3734-[N-Methyl-N-(2-methylthiophen-3-ylcarbonyl)amino]benzoic acid EXAMPLE374 4-[N-Methyl-N-(3-methylthiophene-2-ylcarbonyl)amino]benzoic acidEXAMPLE 375 4-[N-Methyl-N-(2-methylfuran-3-ylcarbonyl)amino]benzoic acidEXAMPLE 376 4-[N-Methyl-N-(3-methylfuran-2-ylcarbonyl)amino]benzoic acidEXAMPLE 377 4-[N-Methyl-N-(phenylacetyl)amino]benzoic acid EXAMPLE 3784-[N-Methyl-N-(2-chlorophenylacetyl)amino]benzoic acid EXAMPLE 3794-[N-Methyl-N-(2-methoxyphenylacetyl)amino]benzoic acid EXAMPLE 3804-[N-Methyl-N-(2-methylphenylacetyl)amino]benzoic acid EXAMPLE 3814-[N-Methyl-N-(cyclohexylcarbonyl)amino]benzoic acid EXAMPLE 3824-[N-Methyl-N-(3-cyclohexenecarbonyl)amino]benzoic acid EXAMPLE 3834-[N-Methyl-N-(cyclohexylacetyl)amino]benzoic acid EXAMPLE 384N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methylbenzamide

A mixture of 0.27 g of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.518 g of4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride, 0.182 g oftriethylamine and 7 ml of tetrahydrofuran is stirred at room temperaturefor 3 hours. To the mixture is added 0.29 g of4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride and 0.10 g oftriethylamine in 2 ml of dichloromethane and the mixture stirred for 2days. The mixture is poured into water and extracted withdichloromethane. The extract is washed with water, 1N HCl, 1N NaHCO₃,brine and dried (Na₂ SO₄). The solution is filtered through a thin padof hydrous magnesium silicate. The filtrate is evaporated in vacuo andthe residue crystallized from dichloromethane-hexane to give 0.38 g ofcrystals, m.p. 168°-170° C.

As described for Example 384, but substituting the appropriate aroylchloride, the following compounds are prepared.

EXAMPLE 385N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-chlorobenzamideEXAMPLE 386N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2,5-dichlorobenzamideEXAMPLE 387N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-chloro-4-methylbenzamideEXAMPLE 388N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methyl-4-chlorobenzamideEXAMPLE 389N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2,4-dimethylbenzamideEXAMPLE 390N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2,3-dimethylbenzamideEXAMPLE 391N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methoxybenzamideEXAMPLE 392N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-trifluoromethoxybenzamideEXAMPLE 393N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2,4-dimethoxybenzamideEXAMPLE 394N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methoxy-4-chlorobenzamideEXAMPLE 395N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methylthiobenzamideEXAMPLE 396N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methyl-3-thiophenecarboxamideEXAMPLE 397N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-3-methyl-2-thiophenecarboxamideEXAMPLE 398N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methyl-3-furanecarboxamideExample 399N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methylbenzeneacetamideEXAMPLE 400N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-chlorobenzeneacetamideEXAMPLE 401N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methoxybenzeneacetamideEXAMPLE 402N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methylbenzeneacetamideEXAMPLE 403N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methyl-3-thiopheneacetamideEXAMPLE 404N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methylcyclohexanecarboxamideEXAMPLE 405N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methylcyclohexylacetamideEXAMPLE 406N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-3-cyclohexenecarboxamideEXAMPLE 407N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-methylphenyl]-2,4-dichlorobenzamide

A mixture of 0.40 g of10,11-dihydro-10-(3-methyl-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazine,0.40 g of 2,4-dichlorobenzoyl chloride and 0.75 g ofdiisopropylethylamine in 50 ml of dichloromethane is stirred at roomtemperature for 16 hours. The mixture is washed with water, dried(MgSO₄) and the solution passed through a thin pad of hydrous magnesiumsilicate. The filtrate is concentrated and hexane added to givecrystals. Recrystallization from dichloromethane-hexane gives 0.52 g ofcrystals, m.p. 213°-215° C.

EXAMPLE 408 1-(2-Nitrophenyl)-1H-pyrrole-2-carboxaldehyde

A sample of 4.7 g of sodium hydride (60% in oil) is washed with hexane(under argon). To the sodium hydride is added 200 ml of dryN,N-dimethylformamide and the mixture is chilled to 0° C. To the mixtureis added 10.11 g of pyrrole-2-carboxaldehyde in small portions. Themixture is stirred 10 minutes and 15.0 g of 1-fluoro-2-nitrobenzeneadded dropwise. After the addition, the mixture is stirred at roomtemperature 16 hours and the mixture concentrated (65° C.) under highvacuum. To the residue is added 400 ml of dichloromethane and themixture washed with 150 ml each of H₂ O, brine and dried (Na₂ SO₄). Thesolvent is removed in vacuo to give a yellow solid. Crystallization fromethyl acetate-hexane (9:1) gives 17.0 g of light yellow crystals, m.p.119°-122° C.

EXAMPLE 409 4,10-Dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine

To an ice cooled mixture of 2.1 g of pyrrole-2-carboxylic acid and 3.2 gof methyl 3-aminothiophene-2-carboxylate in 40 ml of dry dichloromethaneis added 4 g of N,N-dicyclohexylcarbodiimide. The mixture is stirred atroom temperature for 3 hours and filtered. The filter cake is washedwith dichloromethane and then extracted twice with 60 ml of acetone. Theacetone extract is concentrated to dryness to give 0.8 g of solid, m.p.214°-218° C. To a suspension of the preceding compound (1.19 g) in 20 mlof dry tetrahydrofuran is added 0.2 g of sodium hydride (60% in oil).After the hydrogen evolution, the mixture is stirred and refluxed for4.5 hours, cooled and poured into ice-water. The precipitated solid isfiltered and the solid triturated with petroleum ether (bp 30°-60° C.)to give 0.75 g of4,10-dihydro-4,10-dioxo-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine asa solid, m.p. 280°-290° C. The preceding compound (0.362 g) is added toan ice-water cooled solution of 1M diborane in tetrahydrofuran. Themixture is stirred at room temperature for 65 hours. The solution isconcentrated to dryness and ice-water added to the residue. The mixtureis acidified with dilute HCl, stirred and then basified with solidNaHCO₃. The mixture is filtered to give 0.223 g of a solid (foam) m.p.80°-85° C.

EXAMPLE 410 10,11-Dihydro-5H-1,2,4-triazolo[3,4-c][1,4]benzodiapine

A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methyl bromoacetate and1.3 g of potassium carbonate in 12 ml of dry N,N-dimethylformamide isheated at 150°-155° C. for 40 minutes. The cooled mixture is poured intoice-water and the mixture filtered to give 2 g of methyl[N-(2-cyanophenyl)amino]acetate as a yellow solid, m.p. 70°-78° C. Thepreceding compound (2.0 g) is added to a solution of 0.5 g of sodiummethoxide in 50 ml of methanol. The mixture is shaken under anatmosphere of hydrogen with the catalyst Raney-Ni for 19 hours. Themixture is filtered through diatomaceous earth and the filtrateevaporated. Water is added to the residue and the mixture filtered togive 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-3-one as a yellow solid,m.p. 167°-170° C.

A mixture of the preceding compound (1.6 g) and 0.84 g of phosphoruspentasulfide in 10 ml of dry (dried over KOH) pyridine is stirred andheated at 80°-85° C. for 15 minutes. The mixture is poured into waterand stirred for 30 minutes. Filtration gives 1.0 g of1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-3-thione as yellow solid, m.p.150°-153° C.

The preceding compound (0.5 g) and 0.5 g of N-formylhydrazine in 6 ml ofdry n-butanol is refluxed for 16 hours and the solvent removed. Thegummy residue is triturated with cold water and the mixture filtered.The solid is triturated with acetone to give 0.19 g of yellow solid,m.p. 232°-237° C.

EXAMPLE 411 4,5-Dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]-benzodiazepine

A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g)and 0.80 g of N-formylhydrazine in 8 ml of n-butanol is stirred andrefluxed for 18 hours and the solvent removed under vacuum. Ice water isadded to the residual solid and the mixture filtered to give 0.312 g ofa gray solid, m.p. 162°-165° C.

EXAMPLE 412 4,5-Dihydro-6H-imidazo[1,2-a][1,5]benzodiazepine

A mixture of 30 g of acrylic acid, 33 g of o-phenylenediamine is heatedon a steam bath for 1.5 hours and the cooled black mixture trituratedwith ice-water. The aqueous phase is decanted and ice and aqueousammonium hydroxide added to the residue. The mixture is extracted withdichloromethane and the extract concentrated to dryness. The residue istriturated with carbon tetrachloride and filtered. The oily solid istriturated with a small amount of ethanol to give 9.7 g of a solid.Trituration of the solid with ethyl acetate gives2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one as an impure solid, m.p.75°-107° C.

A mixture of the preceding compound (11.3 g) and 5.9 g of phosphoruspentasulfide in 70 ml of dry pyridine is stirred and heated atapproximately 80° C. for 20 minutes. The mixture is poured into waterand the mixture stirred for 30 minutes. Filtration gives 8.6 g of2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione as a solid, m.p.154°-157° C.

A mixture of the preceding compound (0.70 g), 1.0 g of aminoacetaldehydedimethyl acetal and 15 mg of 4-methylbenzenesulfonic acid monohydrate in6 ml of dry n-butanol is refluxed for 4 hours and the solvent removedunder vacuum. The residue is heated (refluxed) with 10 ml of 3Nhydrochloric acid for 55 minutes. Ice is added to the cooled mixture andthe mixture made basic with solid NaHCO₃. The mixture is extracted withdichloromethane and the extract dried (Na₂ SO₄). The solvent is removedto give an orange syrup which solidified on standing. The oily solid istriturated with acetone to give a light yellow solid (0.185 g) m.p.119°-122° C.

EXAMPLE 413 1-(2-Nitrophenyl)-2-pyrroleacetic acid, ethyl ester

To a stirred mixture of 1.88 g of 1-(2-nitrophenyl)pyrrole, 4.80 g ofethyl iodoacetate and 2.22 g of FeSO₄.7H₂ O in 40 ml of dimethylsulfoxide is added dropwise 10 ml of 30% hydrogen peroxide while keepingthe reaction mixture at room temperature with a cold water bath. Themixture is stirred at room temperature for one day. An additional 2.4 gof ethyl iodoacetate, 1.1 g of FeSO₄.7H₂ O and 5 ml of 30% hydrogenperoxide is added and the mixture stirred at room temperature for 1 day.The mixture is diluted with water and extracted with diethyl ether. Theorganic extract is washed with water, brine and dried (Na₂ SO₄). Thesolvent is removed and the residue (2.12 g) chromatographed on silicagel with ethyl acetate-hexane (1:4) as solvent to give 0.30 g of productas a brown gum.

EXAMPLE 414 6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6-one

To a solution of 0.8 mmol of 1-(2-nitrophenyl)-2-pyrroleacetic acid,ethyl ester in 3 ml of ethanol is added stannus chloride dihydrate(SnCl₂. 2H₂ O) in 2 ml of concentrated hydrochloric acid (with coolingin water bath). The mixture is stirred at room temperature for 5 hoursand chilled in an ice bath. To the mixture is added slowly saturatedsodium carbonate solution. The solid which precipitates is filtered andthe solid washed with water and then extracted with ethyl acetate. Theethyl acetate extract is dried (Na₂ SO₄) and the solvent removed to give0.16 g of solid which is triturated with ether to give 0.11 g of productas an off-white solid.

EXAMPLE 415 6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine

To a solution of 0.070 g of6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6-one in 2 ml oftetrahydrofuran is added 0.45 ml of a 2.0M solution ofdiborane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for3 hours, poured into water and make basic with 2N NaOH. Thetetrahydrofuran is removed under vacuum and the residual aqueous mixtureextracted with diethyl ether. The extract is washed with brine, dried(Na₂ SO₄) and the solvent removed to give 0.065 g of a colorless oil;one spot by thin layer chromatography (silica gel) with ethylacetate-hexane (1:2) as solvent (Rf 0.81).

EXAMPLE 41610,11-Dihydro-10-(2-chloro-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 5.0 g of10,11-dihydro-10-(2chloronitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine,15.4 g of stannus chloride and 170 ml of ethanol is heated at 70°-80° C.for 1 hour. The mixture is chilled (ice bath) and made basic with 1MNaHCO₃ solution (350 ml) and then stirred at room temperature for 1hour. The mixture is brought to pH 5 with acetic acid and extracted with500 ml of ethyl acetate and with 300 ml of ethyl acetate. The combinedextract is washed with 250 ml of brine and dried (Na₂ SO₄). The solutionis filtered through a thin pad of hydrous magnesium silicate and thefilter pad washed with ethyl acetate. The filtrate is concentrated todryness and the residue dissolved in 200 ml of hot chloroformmethanol(1:1) and the solution filtered through a thin pad of hydrous magnesiumsilicate. The filtrate is concentrated under vacuum to give 4.36 g(after drying under vacuum at 60° C. overnight) of product as a whitesolid. A sample is recrystallized from chloroformmethanol to give whitecrystals, m.p. 210°-212° C.

EXAMPLE 417 4-[(5-Fluoro-2-methylbenzoyl)amino]benzoic acid

A mixture of 0.60 g of ethyl 4-[(5-fluoro-2-methylbenzoyl)amino]benzoate0.60 ml of 10N NaOH, 25 ml of water and 50 ml of absolute ethyl alcoholis heated on a steam bath for 1 hour, cooled and acidified with aceticacid. The resulting solid is filtered and dried in vacuo at 60°-80° C.to give 0.47 g of the desired product as a solid, m.p. 272°-275° C.

The following Examples are prepared using the conditions of Example 417.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        418         4-[(3-fluoro-2-methylbenzoyl)amino]-                                          benzoic acid, m.p. 309-311° C.                             419         4-[(5-fluoro-2-methylbenzoyl)amino]-2-                                        chlorobenzoic acid, m.p. 247-249° C.                       420         4-[3-fluoro-2-methylbenzoyl)amino]-2-                                         chlorobenzoic acid, m.p. 260-263° C.                       421         4-[[4-fluoro-3-(trifluoromethyl)]benzo-                                       yl]amino]-2-chlorobenzoic acid                                    422         4-[[2-fluoro-3-(trifluoromethyl)]benzo-                                       yl]amino]-2-chlorobenzoic acid                                    423         4-[(2,5-difluorobenzoyl)amino]-2-chloro-                                      benzoic acid                                                      424         4-[(2,5-dichlorobenzoyl)amino]-2-chloro-                                      benzoic acid                                                      425         4-[(2,3-dimethylbenzoyl)amino]-2-chloro-                                      benzoic acid                                                      426         4-[(2,3-dichlorobenzoyl)amino]-2-chloro-                                      benzoic acid                                                      427         4-[(2,5-dimethylbenzoyl)amino]-2-chloro-                                      benzoic acid                                                      428         4-[2,3-difluorobenzoyl)amino]-2-chloro-                                       benzoic acid                                                      ______________________________________                                    

EXAMPLE 429 4-[(2,4-Dichlorobenzoyl)amino]-2-chlorobenzoic acid

To a stirred mixture of 5.19 g of 2-chloro-4-aminobenzoic acid in 150 mlof methylene chloride is added 7.86 g of N,N-diisopropylethylamine and12.67 g of 2,4-dichlorobenzylchloride and stirring continued for 18hours. Water is added to the filtrate and the organic layer dried withNa₂ SO₄ and concentrated in vacuo to give 13.68 g of the desiredproduct, m.p. 171°-175° C.

The following Examples are prepared using the conditions of Example 429.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        430         4-[(2-methylbenzoyl)amino]-2-chloro-                                          benzoic acid, m.p. 196-199° C.                             431         4-[(2-methylbenzoyl)amino]-3,5-di-                                            methylbenzoic acid, m.p. 286-289° C.                       432         4-[(2,4-dichlorobenzoyl)amino]-3,5-                                           dimethylbenzoic acid, m.p. 209-212° C.                     433         4-[(2-methylbenzoyl)amino]-3-chloro-                                          benzoic acid, m.p. 199-202° C.                             434         4-[(2,5-dichlorobenzoyl)amino]-2-                                             chlorobenzoic acid                                                435         4-[(3-fluoro-2-methylbenzoyl)amino]-3-                                        chlorobenzoic acid, m.p. 225-227° C.                       436         4-[(5-fluoro-2-methylbenzoyl)amino]-3-                                        chlorobenzoic acid, m.p. 182-185° C.                       437         4-[(2,3-dimethylbenzoyl)amino]-3-                                             chlorobenzoic acid                                                438         4-[(2,3-dichlorobenzoyl)amino]-3-                                             chlorobenzoic acid                                                439         4-[(2,5-dimethylbenzoyl)amino]-3-                                             chlorobenzoic acid                                                440         4-[[4-fluoro-2-(trifluoromethyl)benzoyl]                                      amino]-3-chlorobenzoic acid                                       441         4-[[3-fluorobenzoyl]amino]-2-chloro-                                          benzoic acid, m.p. 249-252° C.                             442         4-[[2-(trifluoromethyl)benzoyl]amino]-                                        3-chlorobenzoic acid                                              ______________________________________                                    

EXAMPLE 443 Ethyl10,11-dihydro-10-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate

To 25 ml of absolute ethanol is added 0.12 g of sodium metal withstirring followed by 0.68 g of10,11-dihydro-10-(2-chloro-4-nitrobenzoyl)-[3-(trichloroacetyl)]-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

Stirring is continued for 18 hours. The volatiles are removed in vacuoto a residue which is partitioned between methylene chloride and water.The organic layer is separated, dried with Na₂ SO₄ and filtrate heatedon a steam bath while hexane is added to give 0.45 g of the desiredproduct as a solid, m.p. 165°-166° C.

The following Examples are prepared using the conditions of Example 443.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        444         ethyl 10,11-dihydro-10-(3-methyl-4-                                           nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                         benzodiazepine-3-carboxylate, m.p.                                            200-202° C.                                                445         ethyl 10,11-dihydro-10-(2-methyl-4-                                           nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                         benzodiazepine-3-carboxylate                                      446         ethyl 10,11-dihydro-10-(2-chloro-4-                                           nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                         benzodiazepine-3-carboxylate                                      447         ethyl 10,11-dihydro-10-(3-chloro-4-                                           nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                         benzodiazepine-3-carboxylate                                      ______________________________________                                    

EXAMPLE 44810,11-Dihydro-10-(3-methyl-4-nitrobenzoyl)-[3-trichloroacetyl)]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 3.47 g of10,11-dihydro-10(4-nitro-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 50 ml of methylene chloride is added 3.40 g of trichloroaceticanhydride and stirring continued for 18 hours. Water is added and theseparated organic layer washed with saturated sodium bicarbonate, driedwith Na₂ SO₄ and passed through a short pad of hydrous magnesiumsilicate. Hexane is added to the filtrate at the boil to give 4.07 g ofthe desired product as a solid. MASS SPEC (CI) 491(MH⁺).

The following Examples are prepared using the conditions of Example 448.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        449         10,11-dihydro-10-(4-nitrobenzoyl)-[3-                                         (trichloroacetyl)]-5H-pyrazolo[2,1-c]-                                        [1,4]benzodiazepine, m.p. 122-123° C.                      450         10,11-dihydro-10-(2-chloro-4-nitro-                                           benzoyl)-[3-(trichloroacetyl)]-5H-                                            pyrrolo[2,1-c][1,4]benzodiazepine, m.p.                                       149-151° C.                                                ______________________________________                                    

EXAMPLE 45110,11-Dihydro-10-(4-nitrobenzoyl)-[3-(trifluoroacetyl)]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 0.50 g of10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in10 ml of methylene chloride is cooled in an ice bath and 2.0 g oftrifluoroacetic anhydride added. The bath is removed and the reactantsstirred for 18 hrs, partitioned with saturated sodium bicarbonate andthe separated organic layer dried with Na₂ SO₄ then passed through ashort pad of hydrous magnesium silicate. The filtrate is heated at theboil while hexane is added to give 0.40 g of the desired product, m.p.169°-170° C.

The following Examples are prepared using the conditions of Example 451.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        452         10,11-dihydro-10-(2-chloro-4-nitro-                                           benzoyl)[3-(trifluoroacetyl)]-5H-                                             pyrrolo[2,1-c][1,4]benzodiazepine, m.p.                                       151-153° C.                                                453         10,11-dihydro-10-(3-chloro-4-nitro-                                           benzoyl)[3-(trifluoroacetyl)]-5H-                                             pyrrolo[2,1-c][1,4]benzodiazepine                                 454         10,11-dihydro-10-(2-methyl-4-nitro-                                           benzoyl)[3-(trifluoroacetyl)]-5H-                                             pyrrolo[2,1-c][1,4]benzodiazepine                                 ______________________________________                                    

EXAMPLE 45510,11-Dihydro-10-(3-methoxy-4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 5.0 g of 3-methoxy-4-nitrobenzoic acid and 5.0 g of thionylchloride is heated under argon for 1 hour. The volatiles are removed invacuo to give 2.85 g of a 3-methoxy-4-nitrobenzoyl chloride as a residuewhich is dissolved in 50 ml of methylene chloride. To the precedingsolution is added with stirring 1.75 g of N,N-diisopropylethylaminefollowed by 1.84 g of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine. The reaction mixtureis stirred under argon for 18 hours and diluted with saturated sodiumbicarbonate. The organic layer is dried with Na₂ SO₄ and passed througha short pad of hydrous magnesium silicate. While boiling, hexane isadded to the filtrate to give, upon cooling, 3.39 g of the desiredproduct as a solid, m.p. 191°-192° C.

The following Examples are prepared using the conditions of Example 455.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        456         10,11-dihydro-10-(2-methoxy-4-nitro-                                          benzoyl)-5H-pyrrolo[2,1-c][1,4]benzo-                                         diazepine                                                         457         10,11-dihydro-10-(2-methyl-4-nitro-                                           benzoyl)-5H-pyrrolo[2,1-c][1,4]-                                              benzodiazepine                                                    458         10,11-dihydro-10-(3-methoxy-6-chloro-                                         4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                       benzodiazepine                                                    459         10,11-dihydro-10-(3-methoxy-6-methyl-4-                                       nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                         benzodiazepine                                                    ______________________________________                                    

EXAMPLE 46010,11-Dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 3.24 g of10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine,0.35 g of 10% Pd/c and 0.60 g of anhydrous hydrazine in 100 ml ofabsolute ethyl alcohol and heated on a steam bath for 1 hour. The hotreaction mixture is filtered through diatomaceous earth and the filtrateevaporated in vacuo to a residue which is partitioned between methylenechloride and water. The organic layer is dried with Na₂ SO₄ and passedthrough a short pad of hydrous magnesium silicate. Hexane is added tothe filtrate while heating on a steam bath to give 2 g of crystals, m.p.184°-185° C.

The following Examples are prepared using the conditions of Example 460.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        461         10,11-dihydro-10-(4-amino-2-chloro-                                           benzoyl)-5H-pyrrolo[2,1-c][1,4]benzo-                                         diazepine, m.p. 197-199° C.                                462         10,11-dihydro-10-(4-aminobenzoyl)[3-                                          (trifluoroacetyl)]-5H-pyrrolo[2,1-c]-                                         [1,4]benzodiazepine, m.p. 200-206° C.                      463         ethyl 10,11-dihydro-10-(4-amino-3-                                            methylbenzoyl)-5H-pyrrolo[2,1-c]-                                             [1,4]benzodiazepine-3-carboxylate, m.p.                                       210-211° C.                                                464         ethyl 10,11-dihydro-10-(4-aminobenzoyl)-                                      5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-                                       carboxylate, m.p. 174-175° C.                              ______________________________________                                    

EXAMPLE 465N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide

To a stirred solution of 500 mg of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 3 ml of methylene chloride, cooled to 0° C., under argon, is added346 μl of triethylamine followed by the addition of 340 mg of2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride. Thecooling bath is removed and stirring continued for 18 hours. Aftercooling to 0° C., an additional 342 mg of 2-methyl-5-fluorobenzoylchloride in 2 ml of methylene chloride is added. The cooling bath isremoved and stirring continued for 18 hours. The volatiles are removedin vacuo to a residue which is dissolved in 50 ml of methylene chlorideand washed with 20 ml each of water, 2N citric acid, 1M sodiumbicarbonate and brine. The organic layer is dried over Na₂ SO₄ andpassed through a pad of hydrous magnesium silicate. The filtrate isevaporated in vacuo to a residue which is crystallized from ethylacetate-hexane to give 295 mg of the desired product as a white solid,m.p. 170°-180° C.

The following Examples are prepared using the conditions of Example 465with the appropriately substituted aroyl chloride.

    ______________________________________                                        Example No.                                                                              Compound                                                           ______________________________________                                        466        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodia-                                         zepin-10(11H)-ylcarbonyl)phenyl]-3-                                           fluoro-2-methylbenzamide, m.p. 194-208° C.                  467        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2,3-di-                                        methylbenzamide, m.p. 168-170° C.                           468        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2,3-                                           dichlorobenzamide, m.p. 219-222° C.                         469        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2,6-di-                                        chlorobenzamide, m.p. 174-182° C.                           470        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl-3-chlorophenyl]-                                       2-methylbenzamide, m.p. 190-195° C.                         471        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl-3-chlorophenyl)-                                       2,4-dichlorobenzamide, m.p. 144-160° C.                     472        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl-2,6-dimethyl                                           phenyl]-2-methylbenzamide, amorphous                                          solid                                                              473        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl-2,6-dimethyl                                           phenyl]-2,4-dichlorobenzamide, amorphous                                      solid                                                              474        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-3-(tri-                                        fluoromethyl)benzamide, amorphous                                             solid                                                              475        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chloro-                                             phenyl]-3-methylthiophene-2-carboxamide                            476        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-3-                                             chlorothiophene-2-carboxamide, solid;                                         MASS SPEC (CI): 448(M+H)                                           477        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-methoxy-                                            phenyl]-2-methylbenzamide, m.p. 184-                                          186° C.                                                     478        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-methoxy-                                            phenyl]-2,4-dichlorobenzamide, m.p.                                           192-194° C.                                                 479        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-methoxy-                                            phenyl]-3-fluoro-2-methylbenzamide                                            m.p. 203-204° C.                                            480        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2-chloro-                                      5-nitrobenzamide,                                                             m.p. 110-160° C. (amorphous solid)                          267        N-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]-                                       diazepin-4(10H)-ylcarbonyl)phenyl]-                                           2-methylbenzamide, m.p. 162-188° C.                                    (amorphous solid)                                                  274        N-[4-(5H-pyrrolo[1,2-a]thieno(3,2-e]-                                         [1,4]-diazepin-4(10H)-ylcarbonyl)-                                            phenyl]-2,4-dichlorobenzamide, m.p.                                           105-190° C.                                                 ______________________________________                                    

EXAMPLE 481N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-3-fluoro-2-methylbenzamide

To a solution of 1.50 g of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 25 ml of methylenechloride is added 1.23 g of N,N-diisopropylethylamine. While cooling inan ice bath, a solution of 3.08 g of[4-[(2-methyl-5-fluorobenzoyl)amino]-2-chlorobenzoyl chloride in 50 mlof methylene chloride is added. The reaction mixture becomes homogeneousand is stirred at room temperature for 18 hours. Water is added and theseparated organic layer washed with saturated sodium bicarbonate, driedwith Na₂ SO₄ and passed through a short pad of hydrous magnesiumsilicate two times. The methylene chloride is removed in vacuo to give3.81 g of a glass. A sample is crystallized from ethyl acetate to givecrystalline solid, m.p. 200°-205° C.

EXAMPLE 482N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbony)-3-chlorophenyl]-5-fluoro-2-methylbenzamide

To a solution of 1.84 g of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 25 ml of methylenechloride is added 1.30 g of N,N-diisopropylethylamine. While cooling inan ice bath, a solution of 3.45 g of[4-[(2-methyl-5-fluorobenzoyl)amino]-2-chlorobenzoyl chloride in 50 mlof methylene chloride is added. The reaction mixture becomes homogeneousafter 5 minutes and is stirred at room temperature for 18 hours. Wateris added and the separated organic layer washed with saturated sodiumbicarbonate, dried with Na₂ SO₄ and passed through a short pad ofhydrous magnesium silicate. The methylene chloride is removed in vacuoto give 4.60 g of the desired product as a glass. A sample iscrystallized from ethyl acetate to give crystalline solid, m.p.191°-195° C.

EXAMPLE 4834-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid

A solution of 0.92 g of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1.19 g of monomethylterephthaloyl chloride in 20 ml of pyridine is refluxed for 2 hours. Themixture is chilled and 1N HCl added until the pH is 5. The mixture isfiltered and washed with water to give 1.53 g of solid.Recrystallization from dichloromethane-hexane gives crystals, m.p.186°-188° C. of methyl4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoate.

A mixture of 1.83 g of the preceding compound, 8 ml of 2N NaOH and 14 mlof methanol is refluxed for 0.5 hour and then concentrated under vacuum.The residue is extracted with ether and the aqueous layer acifidied with2N citric acid. The mixture is filtered and the solid washed with waterand dried (60° C. under vacuum) to give 1.61 g of crystals, m.p.210°-214° C.

EXAMPLE 484N-(2-Methylphenyl)-4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)benzamide

A mixture of 0.332 g of4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid,0.111 g of triethylamine, 0.107 g of o-toluidine, and 0.15 ml ofdiethylphosphoryl cyanide in 20 ml of dichloromethane is heated on asteam bath overnight. The mixture is washed with water, 1M NaHCO₃, 1NHCl, brine and dried (Na₂ SO₄). The dichloromethane solution is filteredthrough a thin pad of hydrous magnesium silicate and the filtrateconcentrated to dryness. The residue is crystallized fromdichloromethane-hexane to give 0.23 g of white crystals, m.p. 228°-231°C.

EXAMPLE 485N-(2,3-Dimethylphenyl)-4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzamide

A mixture of 0.332 g of4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid,0.222 g of triethylamine, 0.157 g of 2,3-dimethylaniline hydrochloride,0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane isheated on a steam bath for 3 hours. The mixture is washed with H₂ O, 1MNaCHO₃, H₂ O, 1N HCl, brine and dried (Na₂ SO₄). The solution isfiltered through a thin pad of hydrous magnesium silicate and the filtercake washed with dichloromethane. The filtrate is concentrated todryness under vacuum and the residue crystallized fromdichloromethane-hexane to give 0.11 g of crystals, m.p. 239°-240° C.

EXAMPLE 486N-[4-[(4,5-Dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]-benzodiazepin-6-yl)carbonyl)phenyl]-2-methylbenzoate

A mixture of 0.246 g of [4-(2-methylbenzoyl)-amino]benzoyl chloride,0.14 g of 4,5-dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine and 2ml of pyridine is heated on a steam bath for 4.5 hours and heated (oilbath) at 110° C. overnight. The mixture is chilled and poured intowater. The mixture is neutralized with 1N HCl and filtered. The solid iswashed with dichloromethane and the dichloromethane filtrate evaporatedunder vacuum to give 0.151 g of product, MASS SPEC (FAB) 424.2(M+H).

EXAMPLE 487N-[4-(Pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)-phenyl]-2,3-dichlorobenzamide

As described for Example 157, 0.47 g of4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline, 346 μl oftriethylamine and 5 ml of dichloromethane are chilled (ice bath) and0.415 g of 2,3-dichlorobenzoyl chloride in 2 ml of dichloromethaneadded. After stirring overnight, an additional 346 μl of triethylamineis added and an additional 0.415 g of 2,3-dichlorobenzoyl chlorideadded. The mixture is stirred for 2 hours, diluted with 50 ml ofdichloromethane and the solution washed with 20 ml each of H₂ O, 2Ncitric acid, 1M NaHCO₃ and brine. The organic layer is dried (Na₂ SO₄)and filtered through a thin pad of hydrous magnesium silicate and thefiltrate concentrated to dryness. The residue is chromatographed onthick layer silica gel plates with ethyl acetate-hexane (1:1) as solventto give 0.100 g of white solid, m.p. 230°-240° C.

EXAMPLE 48810-[4-[[(2-Chlorophenyl)sulfonyl]amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 0.418 g of 2-chlorobenzenesulfonyl chloride in 5 ml ofdichloromethane, cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineand 0.346 μl of triethylamine. The mixture is stirred at roomtemperature overnight and diluted with 50 ml of dichloromethane. Themixture is washed with 20 ml each of H₂ O, 2N citric acid, 1M NaHCO₃,brine and dried (Na₂ SO₄). The solution is filtered through a thin padof hydrous magnesium silicate and the filtrate concentrated to dryness.The residue is chromatographed on thick layer silica gel plates (4) withthe solvent ethyl acetate-hexane (1:1) to give a solid. Crystallizationfrom ethyl acetate gives 0.165 g of white crystals, m.p. 206°-210° C.

EXAMPLE 489 Methyl4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoate

To a cooled solution of 0.50 g of10,11-di-hydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineand 346 μl of triethylamine in 5 ml of dichloromethane is added 0.394 gof mono methyl terephthaloyl chloride. The mixture is stirred overnightunder argon and diluted with 50 ml of dichloromethane. The mixture iswashed with 20 ml each of H₂ O, 2N citric acid, 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filter cake washed with dichloromethane. Thefiltrate is concentrated to dryness and the residue crystallized fromethyl acetate to give 0.50 g of white crystals, m.p. 224°-228° C.

EXAMPLE 490N-[(Dimethylamino)methyl]-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide

To a suspension under argon of 0.072 g of sodium hydride (60% in oil) in10 ml of tetrahydrofuran is added 0.71 g ofN-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamideand the mixture stirred at room temperature for 1 hour. To the mixtureis added N,N-dimethylmethyleneammonium iodide and the mixture stirred 20hours. The mixture is diluted with diethyl ether (30 ml), filtered andthe filtrate concentrated under vacuum. The residue is triturated withhexane to give 0.76 g of white solid, m.p. 126°-129° C.

EXAMPLE 49110-[4-[(Diphenylphosphinyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo-[2,1-c][1,4]benzodiazepine

A mixture of 0.10 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine0.060 g of triethylamine and 0.12 g of diphenylphosphinyl chloride in 2ml of dichloromethane is stirred at room temperature for 2 hours andthen 1N NaOH is added. The mixture is extracted with ethyl acetate andthe extract washed with brine and dried (Na₂ SO₄). The solvent isremoved and the residue triturated with ether-hexane to give 0.16 g of awhite solid.

EXAMPLE 49210-[4-[Diphenoxyphosphinyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 0.10 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineand 0.060 g of triethylamine in 2 ml of dichloromethane is added 0.14 gof diphenoxyphosphinyl chloride. The mixture is stirred at roomtemperature for 2 hours and 1N NaOH added. The mixture is extracted withethyl acetate and the extract washed with brine and dried (Na₂ SO₄). Thesolvent is removed to give a solid. Trituration with ether-hexane: gives0.20 g of product as a white solid.

EXAMPLE 49310-[4-[[(2,5-Dichlorophenyl)sulfonyl]amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 0.10 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine,0.050 g of triethylamine and 0.083 g of 2,5-dichlorobenzenesulfonylchloride in 2 ml of dichloromethane is stirred at room temperature for 1hour and then 4 mg of 4-(N,N-dimethylamino)pyridine is added. Afteranother hour, 93 mg of 2,5-dichlorobenzenesulfonyl chloride is addedalong with 50 mg of triethylamine. The mixture is stirred at roomtemperature for 2 days and 1N NaOH added. The mixture is extracted withethyl acetate and the extract washed with 50% ammonium chloridesolution, brine and dried (Na₂ SO₄). The solvent is removed to give 0.30g of solid. Trituration with ether-hexane gives 0.26 g of solid. Thissolid is dissolved in a mixture of 5 ml of tetrahydrofuran, 1 ml ofmethanol, 1 ml of 1N NaOH and the mixture stirred for 18 hours at roomtemperature. The organic solvents are removed and the mixture extractedwith ether acetate. The extract is washed with NaHCO₃, brine and dried(Na₂ SO₄). The solvent is removed and the residue (0.16 g) trituratedwith ether to give 0.14 g of yellow solid.

EXAMPLE 49410-[4-[[(Phenylmethyl)sulfonyl]amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 0.10 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineand 0.060 g of triethylamine in 2 ml of dichloromethane is added 0.10 gof α-toluenesulfonyl chloride. The mixture is stirred at roomtemperature for 2 hours and 1N NaOH is added. The mixture is extractedwith ethyl acetate and the extract washed with brine and dried (Na₂SO₄). The solvent is removed and the residue (0.20 g) is chromatographedon silica gel with the solvent ethyl acetate-hexane (3:2) to give 0.080g of product as a white solid and 0.080 g of10-[4-[[bis-(phenylmethyl)sulfonyl]amino]benzoyl]10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineas a white solid. The preceding compound in methanol, 2N NaOH is heatedon a steam bath, the solvent removed and the basic aqueous residueextracted with ethyl acetate to give an additional amount of theproduct.

EXAMPLE 495 Ethyl 4-[(2-methylbenzoyl)amino]-3-chlorobenzoate

A mixture of 8.26 g of ethyl 4-aminobenzoate, 8.26 g ofN-chlorosuccinimide in 50 ml of dichloromethane is refluxed overnight.The mixture is washed with saturated NaHCO₃ solution and dried (Na₂SO₄). The solution is passed through a thin pad of hydrous magnesiumsilicate and the filter cake washed with dichloromethane. The filtrateis concentrated and hexane added. Chilling gives 7.38 g of ethyl3-chloro-4-aminobenzoate, m.p. 82°-83° C.

To the preceding compound (3.66 g), 3.0 g of diisopropylethylamine in 50ml of dichloromethane is added 3.55 g of 2-methylbenzoyl chloride in 10ml of dichloromethane. The mixture is stirred at room temperatureovernight, washed with H₂ O, NaHCO₃ and dried (Na₂ SO₄). The solution ispassed through a thin pad of hydrous magnesium silicate and the filtercake washed with dichloromethane. The filtrate is concentrated anddiluted with hexane. Chilling gives 4.71 g of the product as crystals,129°-130° C.

The following Examples are prepared using the conditions of Example 495.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        496         Ethyl 4-[(2-chlorobenzoyl)amino]-3-                                           chlorobenzoate                                                    497         Ethyl 4-[(2,5-dichlorobenzoyl)amino]-                                         3-chlorobenzoate                                                  498         Ethyl 4-[(2,4-dichlorobenzoyl)amino]-3-                                       chlorobenzoate                                                    499         Ethyl 4-[(3,5-dichlorobenzoyl)amino]-3-                                       chlorobenzoate                                                    500         Ethyl 4-[(2-methyl-4-chlorobenzoyl)-                                          amino]-3-chlorobenzoate                                           501         Ethyl 4-[(2,3-dimethylbenzoyl)amino]-                                         3-chlorobenzoate                                                  502         Ethyl 4-[(2-methoxybenzoyl)amino]-3-                                          chlorobenzoate                                                    503         Ethyl 4-[(2-(trifluoromethoxy)benzoyl]-                                       amino]-3-chlorobenzoate                                           504         Ethyl 4-[(2-methoxy-4-chlorobenzoyl)-                                         amino]-3-chlorobenzoate                                           505         Ethyl 4-[[2-(methylthio)benzoyl]amino]-                                       3-chlorobenzoate                                                  506         Ethyl 4-[(2-methylbenzeneacetyl]amino]-                                       3-chlorobenzoate                                                  507         Ethyl 4-[[4-fluoro-2-(trifluoromethyl)-                                       benzoyl]amino]-3-chlorobenzoate                                   508         Ethyl 4-[[4-fluoro-3-(trifluoromethyl)-                                       benzoyl]amino]-3-chlorobenzoate                                   509         Ethyl 4-[[2-fluoro-3-(trifluoromethyl)-                                       benzoyl]amino]-3-chlorobenzoate                                   510         Ethyl 4-[(3-fluoro-2-methylbenzoyl)-                                          amino]-3-chlorobenzoate                                           511         Ethyl 4-[(2,3-dichlorobenzoyl)amino]-                                         3-chlorobenzoate                                                  512         Ethyl 4-[(4-fluoro-2-methylbenzoyl)-                                          amino]-3-chlorobenzoate                                           513         Ethyl 4-[(5-fluoro-2-methylbenzoyl)-                                          amino]-3-chlorobenzoate                                           514         Ethyl 4-[[2-fluoro-5-(trifluoromethyl)-                                       benzoyl]amino]-3-chlorobenzoate                                   515         Ethyl 4-[[2-(trifluoromethyl)benzoyl]-                                        amino]-3-chlorobenzoate                                           516         Ethyl 4-[[3-(trifluoromethyl)benzoyl]-                                        amino]-3-chlorobenzoate                                           ______________________________________                                    

EXAMPLE 517N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-3-fluoro-2-methylbenzamide

A solution of 2.87 g of 3-fluoro-2-methylbenzoic acid in 25 ml ofthionyl chloride is refluxed for 1.75 hour and the excess thionylchloride removed under vacuum. To the residue is added toluene (severaltimes) and the toluene removed under vacuum after each addition to give3-fluoro-2-methylbenzoyl chloride.

To a solution of 0.25 g of5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepineand 0.0914 g of triethylamine in 6 ml of dichloromethane under argon isadded a solution of 0.156 g of 3-fluoro-2-methylbenzoyl chloride in 1.5ml of dichloromethane. The mixture is stirred overnight at roomtemperature and is washed with H₂ O and saturated NaHCO₃. The organiclayer is treated with activated carbon and filtered through magnesiumsulfate. The filtrate is evaporated, ethyl acetate added and the solventremoved to give 0.38 g of white crystals, m.p. 245°-250° C.: Exact massby mass spectrometry--441.1720(M+H).

EXAMPLE 518N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide

A mixture of 0.185 g of5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.391 g of4-[(5-fluoro-2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 gof diisopropylethylamine in 10 ml of dichloromethane is stirred at roomtemperature overnight. The mixture is washed with H₂ O, 1N HCl, H₂ O, 1MNaHCO₃, brine and dried (Na₂ SO₄). The solution is passed through a thinpad of hydrous magnesium silicate and the filter cake washed withdichloromethane. The filtrate is again passed through a thin pad ofhydrous magnesium silicate. The filtrate is concentrated and the solidcrystallized from ethyl acetate to give crystals, m.p. 137°-140° C.

EXAMPLE 519N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]-2-methylbenzamide

As described for Example 518, a mixture of 0.185 g of5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.369 g of4-[(2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 g ofdiisopropylethylamine in 10 ml of dichloromethane is stirred at roomtemperature to give crystals (from ethyl acetate) m.p. 241°-244° C.

EXAMPLE 520N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]-2,4-dichlorobenzamide

As described for Example 518, a mixture of 0.185 g of5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.472 g of4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride and 0.158 g ofdiisopropylethylamine in 10 ml of dichloromethane is stirred at roomtemperature overnight to give the product (0.27 g) as a pale yellowglass; anal. calc'd: C, 58.7; H, 3.4; N, 11.0; Cl, 20.8 Found C, 57.3;H, 3.3; N, 9.5; Cl, 21.3.

EXAMPLE 5215,10-Dihydro-5-(4-nitro-2-chlorobenzoyl)-4H)-pyrazolo[5,1-c][1,4]benzodiazepine

To a solution of 1.85 g of5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 1.60 g ofdiisopropylethylamine in 50 ml of dichloromethane, cooled in an icebath, is added dropwise a solution of 2.64 g of 4-nitro-2-chlorobenzoylchloride in 25 ml of dichloromethane. The mixture is stirred at roomtemperature overnight and poured into water. The organic layer isseparated and washed with H₂ O, saturated NaHCO₃, H₂ O and dried (Na₂SO₄). The solution is passed through a thin pad of hydrous magnesiumsilicate and the filtrate evaporated. The residue is crystallized fromdichloromethane-hexane to give 3.0 g of crystals, m.p. 197°-199° C.

EXAMPLE 5225,10-Dihydro-5-(4-amino-2-chlorobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine

A mixture of 0.553 g of5,10-dihydro-5-(4-nitro-2-chlorobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine,1.70 g of stannous chloride dihydrate in 20 ml of ethanol is heated at70°-80° C. for 1 hour. The mixture is chilled, made basic with 1M NaHCO₃and then stirred at room temperature for 0.5 hour. The mixture isbrought to pH 5 with acetic acid and extracted (several times) withethyl acetate. The combined extracts are dried (Na₂ SO₄) and passedthrough a pad of hydrous magnesium silicate. The filtrate is evaporatedand the residue dissolved in dichloromethane and the solution passedthrough a thin pad of hydrous magnesium silicate. The filtrate isevaporated in vacuo to give 0.40 g of a glass, m.p. 98°-117° C.; Anal.Calc'd: C, 62.9; H, 4.7; N, 16.3; Cl, 11.6. Found: C, 62.4; H, 4.3; N,15.6; Cl, 11.7.

The following examples are prepared using the conditions of Example 465.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        523         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl]-                                      2-fluorobenzamide, m.p. 223-226° C.                        524         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl]-                                      2-(thiomethylbenzamide), white foam                               525         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                      2,3-dimethylbenzamide, m.p. 189-192° C.                    526         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                      2-chlorobenzamide, m.p. 198-203° C.                        527         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                      4-fluoro-2-chlorobenzamide, m.p.                                              139-141° C.                                                528         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                      2-(trifluoromethyl)benzamide, white foam                          529         N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H-)-ylcarbonyl]-3-chlorophenyl]-                                     2,6-dichlorobenzamide, m.p. 246-248° C.                    ______________________________________                                    

EXAMPLE 530N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophenyl]-2-methylbenzamide

To a mixture of 1.38 g of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1.11 g ofN,N-diisopropylethylamine in 50 ml of dichloromethane is added 2.61 g of4-[(2-methylbenzoyl)amino]-3-chlorobenzoyl chloride in 25 ml ofdichloromethane. The mixture is stirred at room temperature overnightand then washed with H₂ O and saturated NaHCO₃. The organic layer isdried (Na₂ SO₄) and passed through a pad of hydrous magnesium silicate.The filtrate is concentrated, the residue (4.0 g) dissolved indichloromethane and again filtered through a pad of hydrous magnesiumsilicate. The filtrate is evaporated to give the product as a glass(3.62 g). A 1.8 g sample of the glass is crystallized from ethyl acetateto give 1.4 g of crystals, m.p. 176°-178° C.

The following Examples are prepared using the conditions of Example 530.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        531         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,3-dimethylbenzamide                                             532         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,5-dimethylbenzamide                                             533         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,6-dimethylbenzamide                                             534         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-chlorobenzamide                                                 535         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,4-dichlorobenzamide                                             536         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,5-dichlorobenzamide                                             537         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      3,5-dichlorobenzamide                                             538         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl]-                                      3-fluorobenzamide, amorphous solid                                539         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-chloro-4-fluorobenzamide                                        540         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-methyl-4-chlorobenzamide                                        541         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-(methylthio)benzamide                                           542         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-chlorobenzeneacetamide                                          543         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-methylbenzeneacetamide                                          544         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-methylthiophene-3-carboxyamide                                  545         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      3-methylthiophene-2-carboxamide                                   546         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      3-fluoro-2-methylbenzamide, m.p. 230-                                         231° C.                                                    547         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      5-fluoro-2-methylbenzamide, m.p. 178-                                         180° C.                                                    548         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,3-dichlorobenzamide                                             549         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,3-difluorobenzamide                                             550         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      4-fluoro-2-methylbenzamide                                        551         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-methoxybenzamide                                                552         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-(trifluoromethoxy)benzamide                                     553         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-methoxy-4-chlorobenzamide                                       554         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-(trifluoromethyl)benzamide                                      555         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      3-(trifluoromethyl)benzamide                                      556         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,6-dichlorobenzamide                                             557         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2,3,5-trichlorobenzamide                                          558         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-fluoro-5-(trifluoromethyl)benzamide                             559         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      4-fluoro-2-(trifluoromethyl)benzamide                             560         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                      2-fluoro-3-(trifluoromethyl)benzamide                             561         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H-)-ylcarbonyl)-2-chlorophenyl]-                                     2,5-difluorobenzamide                                             562         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl]-5-fluoro-2-methylbenzamide                                563         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl]-2,3-dimethylbenzamide                                     564         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11-H)-ylcarbonyl)-2,3-dichloro-                                        phenyl]-3-fluoro-2-methylbenzamide                                565         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl]-2,4-dichlorobenzamide                                     566         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       hin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl]-2,3-dichlorobenzamide                                     567         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl]-2-methylbenzamide                                         568         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-5-fluoro-2-methylbenzamide                                569         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2,3-dimethylbenzamide                                     570         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-3-fluoro-2-methylbenzamide                                571         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2,4-dichlorobenzamide                                     572         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2,3-dichlorobenzamide                                     573         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2-methylbenzamide                                         574         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2,3-dichlorobenzamide                                     575         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2,5-dichlorobenzamide                                     576         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2-(methylthio)benzamide                                   577         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2-chlorobenzamide                                         578         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2-(trifluoromethyl)benzamide                              579         N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl]-2-(trifluoromethoxy)benzamide                             ______________________________________                                    

EXAMPLE 5802,4-Dichloro-N-[4-[(3-formyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl)carbonyl]phenyl]benzamide

To a solution of 0.48 g of2,4-dichloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl)carbonyl)phenyl]benzamidein 2 ml of N,N-dimethylformamide at 0° C. is slowly added 0.3 ml ofPOCl₃. The mixture is stirred at 0° C. for 30 minutes and at roomtemperature for 1 hour. The final mixture is quenched with ice and madealkaline with 2N NaOH to pH 12. The resulting precipitate is collected,washed with water and dried in vacuo to give 0.55 g of solid. Furtherwashing with 1:2 ether-isopropanol gives 0.50 g of white solid. MS(CI)calculated 503.0774; found 503.0789.

EXAMPLE 5812,4-Dichloro-N-[4-[[3-(hydroxymethyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]benzamide

To a suspension of 39 mg of NaBH₄ in 1 ml of tetrahydrofuran is added0.42 g of2,4-dichloro-N-[4-[(3-formyl-5H-pyrrolo[2,1-a][1,4]benzodiazepin-10(11H)-yl)carbonyl]phenyl]benzamide and the reaction mixture stirred atroom temperature for 18 hours and then quenched with water. Thetetrahydrofuran is evaporated in vacuo and the aqueous residue treatedwith 5 ml of 1N NaOH and extracted with 50 ml of ethyl acetate. Theorganic extract is washed with brine, dried over Na₂ SO₄ and evaporatedto give 0.47 g of a foam. Preparative thick layer chromatography byelution with 2:1 ethyl acetate-hexane gives 0.24 g of white solid.MS(FAB): 488(MH⁺ -OH).

EXAMPLE 5822,4-Dichloro-N-[4-[[3-(1H-imidazol-1-ylmethyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]benzamide

To a suspension of 0.28 g of N,N-dimethylglycine hydrochloride in 5 mlof tetrahydrofuran is added 0.21 g of triethylamine and 0.35 g ofcarbonyldiimidazole. After stirring at room temperature for 30 minutesand then heating at reflux for 18 hours, the tetrahydrofuran isevaporated in vacuo to a residue which is dissolved in ethyl acetate andwashed with water, saturated NaHCO₃ and brine and dried over Na₂ SO₄,filtered and evaporated in vacuo to a residue. The residue is washedwith ether-hexanes (1:1) to give 0.17 g of white solid. MS(FAB):556(M+H).

EXAMPLE 583α-Chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

To a solution of 0.61 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 8 ml of methylene chloride is added 0.30 g of triethylamine followedby 0.47 g of (±)-2-chloro-2-phenylacetyl chloride in 2 ml of methylenechloride. The mixture is stirred at room temperature for 1 hour and thendiluted with 10 ml of 50% NaHCO₃. The methylene chloride is evaporatedand the residue is extracted with ethyl acetate. The separated organiclayer is washed with saturated NaHCO₃ and brine and then dried with Na₂SO₄ followed by filtering through a pad of hydrous magnesium silicate.The filtrate is evaporated to a residue which is stirred withetherhexane to give 0.98 g of pink solid. MS(CI): 456(M+H).

EXAMPLE 584α-[[2-(Dimethylamino)ethyl]thio]-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

A mixture of 0.14 g ofα-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide,0.47 g of 2-dimethylaminoethanethiol hydrochloride in 2 ml of methylalcohol, 0.30 g of triethylamine and 3 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated at 60° C.for 48 hours. The methyl alcohol is evaporated and the residue dilutedwith water. The resulting suspension is filtered and the precipitatewashed with water. The solid is dissolved in ethyl acetate and washedwith saturated NaHCO₃, brine and dried with Na₂ SO₄. The mixture isfiltered and the filtrate evaporated in vacuo to a residue which isstirred with ether-hexane to give 0.15 g of beige solid. MS(CI):525(M+H).

EXAMPLE 585α-[N-(Acetamido)amino]-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

A mixture of 0.14 g ofα-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide,0.17 g of glycinamide HCl, 0.15 g of triethylamine, 3 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1 ml of methylalcohol is heated at 75° C. for 2 days. The methyl alcohol is evaporatedand the residue diluted with water. The resulting suspension is filteredand the precipitate washed with water. The solid is dissolved in ethylacetate and washed with saturated NaHCO₃, brine and dried with Na₂ SO₄.The mixture is filtered and the filtrate evaporated in vacuo to aresidue which is stirred with ether-hexanes to give 0.13 g of tan solid.MS(CI): 494(M+H).

EXAMPLE 586α-(Dimethylamino)-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

A partial solution of ?? g ofα-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamidein 1 ml of methanol is treated with 0.5 ml of dimethylamine and 1 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirringcontinued for 20 hours. The methanol is evaporated and the residuediluted with water. The resulting solid is washed witch water, dissolvedin ethyl acetate and the organic layer washed with saturated NaHCO₃,brine and dried with Na₂ SO₄. The mixture is filtered and the filtrateevaporated in vacuo to give a residue which is stirred with ethylacetate-hexane to give 0.15 g of a beige solid. MS(CI): 465(M+H).

EXAMPLE 587α-(Acetyloxy)-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

To a solution of 0.30 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 5 ml of methylene chloride is added 0.15 g of triethylamine followedby 0.27 g of O-acetylmandelic acid chloride. The mixture is stirred atroom temperature for 1 hour and then diluted with 50% NaHCO₃. Themethylene chloride is evaporated and the residue is extracted with ethylacetate. The separated organic layer is washed with saturated NaHCO₃ andbrine and then dried with Na₂ SO₄ followed by filtering through a pad ofhydrous magnesium silicate. The filtrate is evaporated to a residuewhich is stirred with ether-hexane to give 0.54 g of beige solid.MS(CI): 480(M+H).

EXAMPLE 588 (±)α-Hydroxy-N-[4-(5H-pyrrolo[2,1c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

A solution of 0.34 g ofα-(acetyloxy)-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamidein 2 ml of 1N NaOH and 4 ml of methyl alcohol is stirred at roomtemperature for 30 minutes, diluted with 2 ml of water and evaporated invacuo. The aqueous suspension is extracted with 30 ml of ethyl acetateand the extract washed with brine, dried with Na₂ SO₄ and filteredthrough a pad of hydrous magnesium silicate and evaporated in vacuo to aresidue. The residue is stirred with ether-hexanes to give 0.26 g ofcream colored solid. MS(CI): 438(M+H).

EXAMPLE 589 2-Chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide

To a stirred solution of 0.91 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 10 ml of methylene chloride is added 0.46 g of triethylamine and 36mg of dimethylaminopyridine followed by the slow addition of 0.42 g ofchloroacetyl chloride in 5 ml of methylene chloride. The resultingmixture is stirred at room temperature for 3 hours then partitioned with10 ml of 50% NaHCO₃ and the methylene chloride evaporated in vacuo. Theremaining suspension is filtered, washed with 50% NaHCO₃, H₂ O, EtOAc(2×2 ml), ether (2×5 ml) and dried in vacuo to give 1.14 g of beigesolid. MS(CI): 380(M+H).

EXAMPLE 590N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide

A stirred suspension of 0.19 g of2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamidein 1 ml of methylene chloride is added 0.44 g of morpholine followed by1 ml of 1,3-di-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirringcontinued for 20 hours. The methylene chloride is evaporated and theresidue diluted with water. The resulting suspension is filtered and theprecipitate washed with water. The brown solid is dissolved in 15 ml ofethyl acetate and washed with saturated NaHCO₃, brine and dried with Na₂SO₄. The mixture is filtered and the filtrate evaporated in vacuo togive 0.23 g of a colorless gum which is stirred with ethylacetate-hexanes to give 0.21 g of white solid. MS(CI): 431(M+H).

EXAMPLE 591N-[(2-Chlorophenyl)methyl]-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide

A mixture of 0.11 g ofN-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide,56 mg of O-chlorobenzyl bromide and 0.41 g of K₂ CO₃ in 5 ml ofacetonitrile is heated at reflux for 18 hours. An additional 30 mg ofO-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added followedby heating for 24 hours. The reaction mixture is diluted with water andextracted with ethyl acetate. The organic layer is dried with Na₂ SO₄and evaporated to give 0.18 g of a residue which is purified bychromatography on silica gel with 1:1 ethyl acetate-methylene chlorideto give 80 mg of off white solid. MS(CI): 555(M+H).

EXAMPLE 592 Ethyl10-[4-[(2,4-dichlorobenzoyl)amino]-3-methylbenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate

To a solution of 0.30 g of ethyl10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylatein 20 ml of methylene chloride is added 0.15 g ofN,N-diisopropylethylamine and 0.24 g of 2,4-dichlorobenzoyl chloride.The reaction mixture is stirred at room temperature for 18 hours andwashed with water, saturated NaHCO₃ and dried with Na₂ SO₄. The organiclayer is passed through a pad of hydrous magnesium silicate. Hexane isadded to the filtrate at the boil to give 0.24 g of solid, m.p.174°-184° C.

EXAMPLE 593 Methyl10-[4-(2,4-dichlorobenzoyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate

To 50 ml of absolute methyl alcohol is added 0.15 g of sodium metal.After complete solution, 1.0 g ofN-[4-[[3-(trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl)]carbonyl]phenyl]-2,4-dichlorobenzamideis added and the reaction mixture stirred overnight at room temperature.Methylene chloride is added followed by Na₂ SO₄. The organic layer isfiltered through hydrous magnesium silicate. Hexane is added at the boilto the filtrate to give 0.29 g of solid.

EXAMPLE 594N-[4-[[3-(trifluoroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl)]carbonyl]phenyl]-2-trifluoromethyl)benzamide

To a solution of 1.0 g ofN-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamidein 10 ml of methylene chloride is added 1.0 ml of trifluoroaceticanhydride followed by stirring for 18 hours at room temperature. Thereaction mixture is washed with saturated NaHCO₃, dried with Na₂ SO₄,filtered and hexane added at the boil to give a solid which iscrystallized from methylene chloride-hexane to give 0.89 g of solid,m.p. 248°-250° C.

EXAMPLE 595N-[4-[[3-(Trifluoroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-chlorophenyl]-2-methylbenzamide

To a solution of 0.30 g ofN-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-2-methylbenzamidein 25 ml of methylene chloride is added 0.5 ml of trifluoroaceticanhydride followed by stirring at room temperature for 18 hours. Thereaction mixture is washed with saturated NaHCO₃, dried with Na₂ SO₄,filtered through hydrous magnesium silicate and hexane added to thefiltrate at the boil to give 0.22 g of colorless solid. MS: M+551.

EXAMPLE 596 Ethyl10-[4-[(2,4-dichlorobenzoyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate

To 50 ml of absolute ethyl alcohol is added 0.30 g of sodium metal,followed by the addition of 2.0 g ofN-[4-[[3-(trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)yl]carbonyl]phenyl]-2,4-dichlorobenzamideand the mixture is stirred for 18 hours at room temperature. Thevolatiles are evaporated in vacuo to a residue which is dissolved inmethylene chloride and washed with H₂ O. The organic layer is dried withNa₂ SO₄ and filtered through hydrous magnesium silicate. Hexane is addedto the filtrate at the boil to give a solid which is crystallized frommethylene chloride-hexane to give 0.57 g of a solid. MS (M⁺): 548.2.

EXAMPLE 597 N-[4-[[3-(Trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]-2-trifluoromethyl)benzamide

To a stirred solution of 0.48 g ofN-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamide in 20 ml of methylenechloride is added 0.40 g of trichloroacetic anhydride followed bystirring at room temperature for 18 hours. The reaction mixture iswashed with water and saturated NaHCO₃, dried over Na₂ SO₄ and passedthrough a pad of hydrous magnesium silicate. Hexane is added at the boilto give 0.3:7 g of solid, m.p. 219°-221° C.

EXAMPLE 598N-[4-[[3-(Trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]-2,4-dichlorobenzamide

To a stirred solution of 4.76 g ofN-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamidein 150 ml of methylene chloride is added 3.75 g of trichloroaceticanhydride followed by stirring for 18 hours. The reaction mixture iswashed with water and saturated NaHCO₃, dried over Na₂ SO₄ and passedthrough a pad of hydrous magnesium silicate. The filtrate is evaporatedin vacuo to give 2.91 g of solid.

EXAMPLE 599N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,3,5-trichlorobenzamide

As described for Example 8, 0.50 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis reacted with 0.483 g of 2,3,5-trichlorobenzoyl chloride to give aglass which is crystallized from ethyl acetate to give 0.686 g ofcrystals, m.p. 231°-234° C.

EXAMPLE 600N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]tetrahydrofurane-2-carboxamide

As described for Example 8, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineis reacted with 0.267 g of tetrahydrofurane-2-carbonyl chloride to givea glass which is crystallized from ethyl acetate to give 0.22 g ofcrystals, m.p. 208°-214° C.

The following Examples are prepared using conditions of Example 297 withthe appropriately substituted aroyl chloride.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        601         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                        dichlorophenyl]-2,3-dimethylbenzamide                             602         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                        dichlorophenyl]-2-chlorobenzamide                                 603         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                        dichlorophenyl]-2,4-dichlorobenzamide                             604         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                        dichlorophenyl]-3,5-dichlorobenzamide                             605         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                        dichlorophenyl]-2-methyl-4-chloro-                                            benzamide                                                         606         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-methoxybenzamide                                  607         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-(trifluoromethoxy)                                            benzamide                                                         608         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-(trifluoromethyl)                                             benzamide                                                         609         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2,4-dichlorobenzamide,                                          amorphous white solid, m.p. 134-137° C.                    610         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-(methylthio)benzamide                             611         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-3-fluoro-2-methyl-                                              benzamide, amorphous white solid,                                             m.p. 136-138° C.                                           612         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-5-fluoro-2-methyl-                                              benzamide, amorphous solid, m.p.                                              132-135° C.                                                613         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-4-fluoro-2-methyl-                                              benzamide                                                         614         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-4-fluoro-2-(trifluoro-                                          methyl)benzamide                                                  615         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2,3-dichlorobenzamide                               616         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2,3-difluorobenzamide                               617         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-fluoro-5-(trifluoro-                                          methyl)benzamide                                                  618         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-fluoro-3-(trifluoro-                                          methyl)benzamide                                                  619         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-4-fluoro-2-(trifluoro-                                          methyl)benzamide                                                  620         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2,5-difluorobenzamide                               621         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2,3-difluorobenzamide                               622         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2,5-dimethylbenzamide                               623         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-3-methyl-2-thiophene-                                           carboxamide                                                       624         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-methyl-3-thiophene-                                           carboxamide                                                       625         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-methyl-3-furane-                                              carboxamide                                                       626         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-3-methyl-2-furane-                                              carboxamide                                                       627         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-chlorobenzeneacetamide                            628         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-2-methylbenzeneacetamide                            629         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-4-fluoro-3-(trifluoro-                                          methyl)benzamide                                                  630         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-3-fluoro-2-methyl-                                              benzamide                                                         631         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2,3-dichlorobenzamide                               632         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2,3-difluorobenzamide                               633         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-4-fluoro-2-methyl-                                              benzamide                                                         634         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-5-fluoro-2-methyl-                                              benzamide                                                         635         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2-fluoro-5-(trifluoro-                                          methyl)benzamide                                                  636         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2-methylbenzamide                                   637         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2-chlorobenzamide                                   638         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2,3-dimethylbenzamide                               639         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2,5-dimethylbenzamide                               640         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2-methoxybenzamide                                  641         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2-(trifluoromethoxy)-                                           benzamide                                                         642         N-[4-[(6,7-Dihydro-5-H-pyrrolo[1,2-a]-                                        [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2-methoxy-4-chloro-                                             benzamide                                                         643         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2,6-dichlorobenzamide                               644         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2-(methylthio)benzamide                             645         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2-(trifluoromethyl)-                                            benzamide                                                         646         [4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                           [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-3-(trifluoromethyl)-                                            benzamide                                                         647         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          chlorophenyl]-2,3,5-trichlorobenzamide                            648         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          methoxyphenyl]-3-fluoro-2-methylbenz-                                         amide                                                             649         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          methoxyphenyl]-5-fluoro-2-methylbenz-                                         amide                                                             650         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          methoxyphenyl]-4-fluoro-2-methylbenz-                                         amide                                                             651         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          methoxyphenyl]-2,4-dichlorobenzamide                              652         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          methoxyphenyl]-2,3-dimethylbenzamide                              653         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-3-                                          methoxyphenyl]-3-fluoro-5-(trifluoro-                                         methyl)benzamide                                                  654         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          methoxyphenyl]-3-fluoro-2-methylbenz-                                         amide                                                             655         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          methoxyphenyl]-5-fluoro-2-methylbenz-                                         amide                                                             656         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          methoxyphenyl]-4-fluoro-2-methylbenz-                                         amide                                                             657         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          methoxyphenyl]-2,4-dichlorobenzamide                              658         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          methoxyphenyl]-2,3-dimethylbenzamide                              659         N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                         [1,5]benzodiazepin-5-yl)carbonyl]-2-                                          methoxyphenyl]-3-fluoro-5-(trifluoro-                                         methyl)benzamide                                                  ______________________________________                                    

EXAMPLE 660N-[4-[[[3-[-[(Dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]-2-methylbenzamide

To a stirred solution of 0.842 g of2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzamidein 25 ml of 1:1 methanoltetrahydrofuran is added 10 ml of 35%formaldehyde and 10 ml of 30% N,N-dimethylamine at 0° C. After 2 dropsof acetic acid is added, the reaction mixture is stirred at roomtemperature for 16 hours. The reaction mixture is concentrated in vacuoto a residue which is dissolved in chloroform and washed with water. Theorganic layer is dried with Na₂ SO₄ and evaporated in vacuo to aresidue. The residue is chromatographed on silica gel with 10:1 ethylacetate-methanol as eluent to give 0.800 g of the desired product, M⁺H:479.

The following products are prepared by using the condition of Example660 and by using the appropriately substituted benzamide.

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        661         N-[4-[[3-(1-piperidinylmethyl)-5H-                                            pyrrolo[2,1-c][1,4]benzodiazepin-                                             10(11H)-yl]carbonyl]phenyl]-2-methyl-                                         benzamide, solid; mass spectrum (M.sup.+ H)                                   518                                                               662         N-[4-[[3-(4-morpholinomethyl)-5H-                                             pyrrolo[2,1-c][1,4]benzodiazepin-                                             10(11H)-yl]carbonyl]phenyl]-2-methyl-                                         benzamide, solid; mass spectrum (M.sup.+ H)                                   521                                                               663         N-[4-[[3-[[4-(phenylmethyl)-1-pipera-                                         zinyl]methyl]-5H-pyrrolo[2,1-c][1,4]-                                         benzodiazepin-10(11H)-yl]carbonyl]-                                           phenyl]-2-methylbenzamide, solid; mass                                        spectrum (M.sup.+ H) 610                                          664         N-[4-[[3-[(dimethylaminomethyl]-                                              5H-pyrrolo[2,1-c][1,4]benzodiazepin-                                          10(11H)-yl]carbonyl]phenyl]-2,4-di-                                           chlorobenzamide, solid; mass spectrum                                         (M.sup.+ H) 535                                                   665         N-[4-[[3-(1-pyrrolidinylmethyl)-                                              5H-pyrrolo[2,1-c][1,4]benzodiazepin-                                          10(11H)-yl]carbonyl]phenyl)-2,4-di-                                           chlorobenzamide, solid; mass spectrum                                         (M.sup.+ H) 561                                                   666         N-[4-[[3-(4-morpholinomethyl)-5H-                                             pyrrolo[2,1-c][1,4]benzodiazepin-                                             10(11H)-yl]carbonyl]phenyl]-2,4-di-                                           chlorobenzamide, solid; mass spectrum                                         (M.sup.+ H) 576                                                   667         N-[4-[[3-[(diethylamino)methyl]-5H-                                           pyrrolo[2,1-c][1,4]benzodiazepin-                                             10(11H)-yl]carbonyl]phenyl]-2,4-di-                                           chlorobenzamide, solid; mass spectrum                                         (M.sup.+ H) 562                                                   668         N-[4-[[3-[(dimethylamino)methyl]-5H-                                          pyrrolo[2,1-c][1,4]benzodiazepin-                                             10(11H)-yl]carbonyl]-3-chlorophenyl]-                                         5-fluoro-2-methylbenzamide, solid;                                            mass spectrum (M.sup.+ H) 531                                     669         N-[4-[[3-[(dimethylamino)methyl]-5H-                                          pyrrolo[2,1-c][1,4]benzodiazepin-                                             10(11H)-yl]carbonyl]-3-chlorophenyl]-                                         2-methylbenzamide, solid; mass spectrum                                       (M.sup.+ H) 513                                                   ______________________________________                                    

EXAMPLE 670N-[4-[(3-Acetyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]-2,4-dichlorobenzamide

A stirred solution of 0.954 g ofN-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamidein 25 ml of methylene chloride and 5 ml of acetic anhydride is heated atreflux for 24 hours. The volatiles are evaporated in vacuo to a residuewhich is purified by column chromatography on silica gel by elution withethyl acetatehexane (7:3) to give 0.800 g of a white solid; massspectrum (M⁺ H)519.

EXAMPLE 671 1-[2-Nitro-5-(ethoxycarbonl)benzyl]-pyrrole-2-carboxaldehyde

To a stirred slurry of 2.2 g of sodium hydride (60% in oil, washed withhexane) in tetrahydrofuran is added at 0° C. a solution of 4.5 g ofpyrrole-2-carboxaldehyde in 25 ml of tetrahydrofuran. After the additionis complete, a solution of 15 g of ethyl 4-nitro-3-bromomethylbenzoatein 30 ml of dry. tetrahydrofuran is slowly added under nitrogen. Thereaction mixture is stirred at 20° C. for 8 hours and carefully quenchedwith water. The reaction mixture is extracted with chloroform which iswashed with water, dried with Na₂ SO₄ and concentrated in vacuo to give12 g of the desired product as a solid; mass spectrum (M⁺ H) 349.

EXAMPLE 6721-[2-Nitro-4-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde

The conditions of Example 671 are used with ethyl3-nitro-4-bromomethylbenzoate to give 13.0 g of the desired product as asolid; mass spectrum (M⁺ H)349.

EXAMPLE 673 Ethyl10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate

A solution of 10.0 g of1-[2-nitro-5-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde in 150 mlof absolute ethanol containing 1.0 g of 10% Pd/c is hydrogenated in aParr apparatus for 16 hours under 40 psi of hydrogen. The reactionmixture is filtered through a pad of diatomaceous earth and the filtrateconcentrated in vacuo to a residue of 5.5 g of the desired product as asolid; mass spectrum (M⁺ H) 255.

EXAMPLE 674 Ethyl10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylate

The hydrogenation conditions of Example 673 are used with1-[2-nitro-4-(ethoxycarbonyl)benzyl]pyrrole-2-carboxaldehyde to give 5.0g of the desired product as a solid; mass spectrum (M⁺ H)255.

EXAMPLE 675 Ethyl10,11-Dihydro-10-4-[(2-methylbenzoyl)amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate

A solution of 1.2 g of ethyl10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate in 100ml of methylene chloride is cooled to 0° C. and 10 ml of triethylamineadded followed by 1.5 g of 4-[(2-methylbenzoyl)amino)benzoyl chloride.The reaction mixture is stirred at room temperature for 18 hours andconcentrated in vacuo to a residue which is partitioned between waterand chloroform. The organic layer is dried over Na₂ SO₄ and concentratedin vacuo to a residue. The residue is purified by column chromatographyon silica gel by elution with 40% ethyl acetate-hexane to give 1.0 g ofthe desired product as a solid; mass spectrum (M⁺ H)494.

EXAMPLE 676 Ethyl10,11-Dihydro-10-[4-[(2-methylbenzoyl)amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-8-carboxylate

The conditions of Example 675 are used with ethyl10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylate to give1.2 g of the desired product as a solid; mass spectrum (M⁺ H)494.

The subject compounds of the present invention are tested for biologicalactivity as follows:

EXAMPLE 67710,11-Dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine

A 292 mg sample of sodium hydride in oil is washed, under argon, withpentane. The residue is diluted with 17 ml of dioxane and then 1.35 g of10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine is added. Thereaction mixture is warmed slightly until the hydrogen evolution ceases.To the cooled reaction mixture is added a solution of 1.36 g ofp-nitrobenzoyl chloride in 45 ml of dioxane and the mixture is stirredat room temperature for 18 hours. The solvent is evaporated in vacuo andthe residue is heated with CHCl₃, filtered hot and the filter cakewashed with hot CHCl₃. The combined CHCl₃ layers are washed with water,saturated NaHCO₃, treated with activated charcoal, filtered through apad of MgSO₄ and the filtrate evaporated in vacuo to give 1.82 g ofbrown solid residue. The residue is purified by flash chromatography byelution with CHCl₃ --MeOH to give 630 mg of the desired product as asolid. HR FABMS:(M+H)=335.3433.

EXAMPLE 67810,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine

A mixture of 0.550 g of10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][[1,4]benzodiazepineand 1.86 g of SnCl₂.2H₂ O in 22 ml of ethyl alcohol is refluxed for 1hour under argon. The mixture is diluted with water and then a solutionof 10% NaHCO₃ is added until the reaction mixture is basic. Additionalethyl alcohol is added and reaction mixture evaporated in vacuo to givea residue which is triturated with 1:1 CHCl₃ --CH₃ OH several times andfiltered. The filtrates are combined, treated with activated carbon andfiltered through diatomaceous earth. The filtrate is evaporated in vacuoto give 680 mg of tan crystalline solid. The solid is stirred inethanol, water and 10% NaHCO₃ to pH=8, for 5 hours and extracted withCHCl₃ three times. The combined extracts are treated with activatedcarbon, filtered through MgSO₄ and evaporated in vacuo to give 370 mg oftan crystalline solid. CIMS(CH₄):MH⁺ =305.

EXAMPLE 679N-[4-(5H-Imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide

A slurry of 0.330 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepinein 15 ml of dioxane is stirred and warmed slightly to obtain a nearlycomplete solution. The reaction mixture is cooled to room temperatureand 43 mg of sodium hydride in oil added. The mixture is warmedslightly. Gas evolution stops in a few minutes. The reaction mixture iscooled to room temperature and 153 μl of 2,4-dichlorobenzoyl chloride in2.5 ml of dioxane added. An additional 3.5 ml of dioxane is added andthe reaction mixture stirred at room temperature for 2 days. Thevolatiles are evaporated in vacuo to a residue which is partitionedbetween water and chloroform. The organic layer is separated and theaqueous phase extracted with chloroform two more times. The combinedorganic layers are trated with activated carbon and filtered throughMgSO₄. The filtrate is evaporated in vacuo to a tan foam which ispurified by flash chro- matography on silica gel by elution with CHCl₃and 3-7% CH₃ OH in chloroform to give 310 mg of tan foam.

EXAMPLE 6806,7-Dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine

To a solution of 0.28 g of6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 6 ml of methylenechloride is added 0.30 g of triethylamine followed by 0.50 g of2-chloro-4-nitrobenzoyl chloride in 0.5 ml of methylene chloride. Thereaction mixture is stirred at room temperature for 1 hour then quenchedwith 5 ml of saturated NaHCO₃. The methylene chloride is evaporated invacuo and the residue is diluted with 5 ml of water and extracted with20 ml of ethyl acetate. The organic layer is separated, washed withsaturated NaHCO₃ and brine, dried with Na₂ SO₄ and evaporated in vacuoto give 0.59 g of a yellow foam which is triturated with ether-hexanesto give 0.56 g of the desired product as off-white solid. MS(CI):368(M+H)(Cl³⁵) 370(M+H)(Cl³⁷)

EXAMPLE 6816,7-Dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepin

To a solution of 0.50 g of6,7-dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepinein 10 ml of ethyl alcohol and 2 ml of tetrahydrofuran is added 2.35 g ofSnCl₂.2H₂ O and the mixture stirred at 55° C. for 30 minutes. Thesolvents are evaporated in vacuo to a residue which is stirred with 20ml of 1N NaOH and 40 ml of ethyl acetate for 15 minutes and filteredthrough diatomaceous earth. The filter pad is washed with 2×10 ml ofethyl acetate and the combined extracts washed with brine, dried (Na₂SO₄) and evaporated in vacuo to give 0.47 g of solid residue which istriturated with ether-hexane to give 0.43 g of light yellow crystallinesolid. MS(CI): 338(M+H, Cl³⁵) 340(M+H, Cl³⁷)

EXAMPLE 682N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-3-fluoro-2-methylbenzamide

To a mixture of 0.10 g of6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepineand 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 gof 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. Themixture is stirred for 2 hours at room temperature and then 2 ml of 1NNaOH added. The volatiles are evaporated under vacuum and the residuedissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixtureis stirred for 2 hours and evaporated and the residue diluted with 2 mlof 1N NaOH and 5 ml of water. The mixture is extracted with ethylacetate (15 ml) and the extract washed with brine and dried (Na₂ SO₄).The solvent is removed and the residue triturated with diethylether-hexane to give 0.15 g of white solid: Mass Spectrum (CI)474(M+H,Cl³⁵); 476(M+H, Cl³⁷).

EXAMPLE 683N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-2,4-dichlorobenzamide

To a mixture of 0.10 g of6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepineand 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.10 gof 2,4-dichlorobenzoyl chloride in 0.5 ml of dichloromethane. Themixture is stirred at room temperature for 2 hours and 2 ml of 1N NaOHis added. The volatiles are removed under vacuum and to the residue isadded 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture isstirred at room temperature for 2 hours and the volatiles removed. Tothe residue is added 2 ml of 1N NaOH and 5 ml of H₂ O. The mixture isextracted with ethyl acetate and the extract washed with brine and dried(Na₂ SO₄). The solvent is removed and the solid triturated with diethylether-hexane to give 0.15 g of white solid, Mass Spectrum (CI): 510(M+H,Cl³⁵).

EXAMPLE 684N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(1H-[1,2,4]-triazol-1-yl)acetamide

To a suspension of 0.20 g of 1,2,4-triazole sodium in 1 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is added 0.10 g of2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamidein 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone followedby stirring at room temperature for 3 hours. The reaction mixture isquenched with 15 ml of water and the resulting solid is collected,washed with water and hexanes to give 70 mg of the desired product as atan solid. MS(CI): 413(M+H).

EXAMPLE 685N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(2-formyl-1-pyrrolo)acetamide

To a suspension of 72 mg of sodium hydride (60% in oil) in 5 ml oftetrahydrofuran is added 0.14 g of pyrrole-2-carboxaldehyde. The mixtureis stirred for 1 hour at room temperature and 94 mg of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 0.19 g of2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamideadded. The mixture is stirred at room temperature, water added and thetetrahydrofuran evaporated in vacuo. The resulting suspension isfiltered and the precipitate washed with water and hexanes. Thecollected solid is purified by column chromatography on silica gel byelution with 3:2 ethyl acetate-hexanes to give 50 mg of pink solid.MS(CI): 439(M+H).

EXAMPLE 686N-[4-3-Chloro-4H-pyrazolo[5,1-c][1,4]benzodiazepin-5-(10H)-ylcarbonyl)phenyl]-2-methyl-5-fluorobenzamide

A mixture of 356 mg ofN-[4H-pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamideand 122 mg of N-chlorosuccinimide in 5 ml of methylene chloride isrefluxed on a steam bath for 3 hours. The reaction mixture is washedwith saturated NaHCO₃, H₂ O and brine, then dried over Na₂ SO₄ andpassed through a pad of hydrous magnesium silicate. The filtrate isevaporated in vacuo to give 190 mg of the desired product as a solid.

The following examples are prepared using the conditions of Example 465.

    ______________________________________                                        Example No.                                                                              Compound                                                           ______________________________________                                        687        N-[4-(5H-pyrrolo[2,1-c)[1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2-bromo-                                       benzamide, white solid                                             688        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2-                                             (acetoxy)benzamide, light yellow solid                             689        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H-)-ylcarbonyl)phenyl]-2-                                            hydroxybenzamide, light yellow solid                               690        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-1-                                             naphthylcarboxamide, white solid                                   691        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-methylphenyl]-                                      2-methylbenzamide, amorphous solid                                 692        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2-chloro-                                      4-fluorobenzamide, white foam                                      693        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2-(tri-                                        fluoromethyl)-4-fluorobenzamide, white                                        solid                                                              694        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-methylphenyl]-                                      5-fluoro-2-methylbenzamide, m.p. 180-                                         182° C.                                                     695        N-[4-(5H-pyrrolo[2,1-c]1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-methoxy-                                            phenyl]-5-fluoro-2-methylbenzamide,                                           amorphous solid                                                    696        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl]-2-fluoro-4-(trifluoromethyl)                                          benzamide, m.p. 140-154° C.                                 697        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl]-2-methylbenzeneacetamide,                                             white glass                                                        698        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl]-2-fluoro-6-(trifluoromethyl)                                          benzamide, white solid, m.p. 150-230° C.                    699        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl]-2-fluoro-3-(trifluoromethyl)                                          benzamide, white glass                                             700        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl]-2-chloro-5-(methylthio)                                               benzamide, white crystals, m.p.                                               124-134° C.                                                 701        N-[4-(5H-pyrrolo[2,1-c][1.4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl]-2,5-dimethylbenzamide,                                                crystalline solid, m.p. 253-255° C.                         702        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl]-2-chloro-3,4-dimethoxybenzamide,                                      yellow foam                                                        703        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-6-chloro-3-                                           methoxyphenyl]-2-methylbenzamide,                                             crystals, m.p. 214-215° C.                                  704        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-methoxy                                             phenyl]-2,5-dimethylbenzamide,                                                crystals, m.p. 174-175° C.                                  705        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2-chloro-                                      3,4-dimethoxybenzamide, white crystals,                                       m.p. 242-244° C.                                            706        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl]-2,5-                                           dimethylbenzamide, crystals,                                                  m.p. 158-160° C.                                            707        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl]-                                      2-(trifluoromethyl)-4-fluorobenzamide,                                        white glass                                                        ______________________________________                                    

EXAMPLE 708 Methyl4-[2-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)ethyl]benzoate

A 0.876 g sample of 60% sodium hydride in oil is washed with hexanefollowed by the addition of 60 ml of dry N,N-dimethylformamide. Thereaction mixture is stirred for 1 hour under argon at room temperatureafter the addition of 4.73 g ofα-(2-chlorophenyl)-4-morpholineacetonitrile. To the reaction mixture isadded 4.58 g of methyl 4-(bromomethyl)benzoate and stirring continuedfor 3 hours. Several drops of acetic acid is added to ice water and thereaction quenched. The pH is 3-4 and saturated NaHCO₃ added to adjustthe pH to 6-7. Upon cooling a solid forms which is filtered, washed withwater and dried to give 5.92 g of yellow solid. Crystallization frommethylene chloride-hexane gives 2.10 g of the desired product as acrystalline solid, m.p. 116°-118° C.

EXAMPLE 709 Methyl 4-[2-(2-chlorophenyl)-2-oxoethyl]benzoate

A mixture of 1.0 g of methyl[4-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)ethyl]benzoate and 14 ml ofwater is heated at reflux for 20 minutes then poured over crushed ice.After stirring for 15 minutes the resulting solid is collected, washedwith water and air dried to give 0.63 g of tan solid, m.p. 40°-42° C.

EXAMPLE 710 4-[2-(2-Chlorophenyl)-2-oxoethyl]benzoic acid

A mixture of 18.78 g of methyl 4-[2-(2-chlorophenyl)-2-oxoethyl]benzoatein 288.8 ml of CH₃ OH, 72.2 ml of water and 5.2 g of NaOH is refluxedfor 3 hours then acidified with 2N citric acid. The reaction mixture isevaporated in vacuo to remove the CH₃ OH. The aqueous phase is extractedwith CH₂ Cl₂ and acidified with 1N HCl. The resulting solid is collectedand dried under vacuum to give 17.27 g of the desired product, m.p.168°-172° C.

EXAMPLE 711 3-Methoxy-4-nitrobenzoyl chloride

A stirred suspension of 1.0 g of 3-methoxy-4-nitrobenzoic acid and 1.40ml of thionyl chloride is heated to reflux for 2 hours. The mixture iscooled to room temperature, 2 ml of iso-octane added and the mixtureevaporated in vacuo to a solid residue. The residue is washed withiso-octane (2×2 ml), dried in vacuo to give 1.08 g of cream coloredsolid.

EXAMPLE 71210,11-Dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 0.55 g of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylenechloride is added 0.55 g of triethylamine followed by 0.97 g of3-methoxy-4-nitrobenzoyl chloride. The reaction mixture is stirred atroom temperature for 2 hours and then quenched with 10 ml of 1N NaOH.The methylene chloride layer is evaporated and the resulting suspensionfiltered. The precipitate is washed with 1N NaOH (2×5 ml), water (3×5ml) and hexane (2×5 ml). The collected solid is dried in vacuo to give1.13 g of off-white solid. MS (CI): 364(M+H).

EXAMPLE 71310,11-Dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 0.91 g of10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine,4.51 g of SnCl₂.2H₂ O, 6 ml of ethyl alcohol, 6 ml of tetrahydrofuranand 16 ml of methylene chloride is stirred at 50° C. for 2 hours. Thesolvents are evaporated in vacuo and the residue dissolved in 80 ml ofethyl acetate. The solution is treated with 50 ml of 1N NaOH withstirring for 30 minutes. The resulting suspension is filtered throughdiatomaceous earth. The pad is washed with ethyl acetate (3×15 ml). Thecombined ethyl acetate solutions are washed with brine, dried (Na₂ SO₄),filtered through hydrous magnesium silicate and evaporated in vacuo to0.99 g of residue which is stirred with ether-hexanes to give 0.90 g ofcream colored solid. MS(CI): 334(M+H).

EXAMPLE 71410,11-Dihydro-10-[4-[(3-methylpropyloxycarbonyl)amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 0.15 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 2 ml of methylene chloride is added 0.10 g of triethylamine followedby 0.10 g of isobutylchloroformate. The reaction mixture is stirred for3 hours and then quenched with 1N NaOH. The organic layer is evaporatedin vacuo to a residue which is stirred in 5 ml of tetrahydrofuran for 1hour, then evaporated in vacuo to a residue. The residue is extractedwith ethyl acetate-methylene chloride, washed with brine, dried (Na₂SO₄), filtered through hydrous magnesium silicate and evaporated invacuo to give a residue which is stirred with ethyl acetate-methylenechloride to give 0.22 g of cream colored solid. MS (CI): 404(M+H).

EXAMPLE 71510,11-Dihydro-10-[4-(pentanoyl)aminobenzoyl)]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 0.15 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 2 ml of methylene chloride is added 0.10 g of triethylamine followedby 0.09 g of valeryl chloride. The reaction mixture is stirred for 3hours and then quenched with 4 ml of 1N NaOH. The methylene chloride isevaporated in vacuo and the residue dissolved in 5 ml of tetrahydrofuranfor 1 hour and evaporated in vacuo to a residue. The residue isextracted with ethyl acetate-methylene chloride, washed with brine andthe organic layer dried (Na₂ SO₄), filtered through hydrous magnesiumsilicate, and evaporated in vacuo to give 0.23 g of a residue which isstirred with ether-hexanes to give 0.19 g of a white solid. MS (CI):388(M+H).

EXAMPLE 71610,11-Dihydro-10-[4-[(3-methylbutanoyl)amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 0.10 g of10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 1 ml of methylene chloride is added 0.06 g of triethylamine followedby 0.05 g of iso-valeryl chloride. The reaction mixture is stirred for 3hours and then quenched with 1N NaOH. The organic layer is evaporated invacuo to a residue which is stirred in 5 ml of tetrahydrofuran for 1hour, then evaporated in vacuo to a residue. The residue is extractedwith ethyl acetate-methylene chloride, washed with brine, dried (Na₂SO₄), filtered through hydrous magnesium silicate and evaporated invacuo to give 0.15 g of residue which is stirred with ether-hexane togive 0.13 g of light yellow solid. MS(CI): 418(M+H).

EXAMPLE 71710,11-Dihydro-10-[3-methoxy-4-[(butylsulfonyl)amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 0.10 g of10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinein 2 ml of methylene chloride is added 60 mg of triethylamine followedby a solution of 56 mg of n-butylsulfonyl chloride in 0.5 ml ofmethylene chloride. After stirring at room temperature for 2 hours, thereaction mixture is evaporated in vacuo to a residue which is dissolvedin methyl alcohol, stirred for 1 hour and evaporated in vacuo to aresidue which is treated with 2 ml of NH₄ Cl and extracted with 15 ml ofethyl acetate. The organic: extract is washed with saturated NaHCO₃,brine, dried (Na₂ SO₄), filtered through hydrous magnesium silicate andthe filtrate evaporated to a residue. The residue is stirred withether-hexanes to give 0.14 g of light yellow solid. MS (CI): 454(M+H).

UTILITY TESTING

Binding Assay to Rat Hepatic V₁ Receptors

Rat liver plasma membranes expressing the vasopressin V₁ receptorsubtypes are isolated by sucrose density gradient according to themethod described by Lesko et al., (1973). These membranes are quicklysuspended in 50.0 mM Tris.HCl buffer, pH 7.4, containing 0.2% bovineserum albumin (BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) andkept frozen at -70° C. until used in subsequent binding experiments. Forbinding experiments, the following is added to the wells of a ninety-sixwell format microtiter plate: 100 μl of 100.0 mM Tris.HCl buffercontaining 10.0 mM MgCl₂, 0.2% heat inactivated BSA and a mixture ofprotease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;1,10-phenanthroiine, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF, 20.0 μl of [phenylalanyl-3,4,5, -³ H] vasopressin (S.A. 45.1Ci/mmole) at 0.8 nM, and the reaction initiated by the addition of 80 μlof tissue membranes containing 20 μg of tissue protein. The plates arekept undisturbed on the bench top at room temperature for 120 min. toreach equilibrium. Non-specific samples are assayed in the presence of0.1 μM of the unlabeled antagonist phenylalanylvasopressin, added in20.0 μl volume.

For test compounds, these are solubilized in 50% dimethylsulfoxide(DMSO) and added in 20.0 μl volume to a final incubation volume of 200μl . Upon completion of binding, the content of each well is filteredoff, using a Brandel® cell Harvester (Gaithersburg, Md.). Theradioactivity trapped on the filter disk by the ligand-receptor complexis assessed by liquid scintillation counting in a Packard LS Counter,with an efficiency of 65% for tritium. The data are analyzed for IC₅₀values by the LUNDON-2 program for competition (LUNDON SOFTWARE, Ohio).

Binding Assay to Rat Kidney Medullary V₂ Receptors

Medullary tissues from rat kidneys are dissected out, cut into smallpieces and soaked in a 0.154 mM sodium chloride solution containing 1.0mM EDTA with many changes of the liquid phase, until the solution isclear of blood. The tissue is homogenized in a 0.25M sucrose solutioncontaining 1.0 mM EDTA and 0.1 mM PMSF using a Potter-Elvehjemhomogenizer with a teflon pestle. The homogenate is filtered throughseveral layers (4 layers) of cheese cloth. The filtrate is rehomogenizedusing a dounce homogenizer, with a tight fitting pestle. The finalhomogenate is centrifuged at 1500× g for 15 min. The nuclear pellet isdiscarded and the supernatant fluid recentrifuged at 40,000× g for 30min. The resulting pellet formed contains a dark inner part with theexterior., slightly pink. The pink outer part is suspended in a smallamount of 50.0 mM Tris. HCl buffer, pH 7.4. The protein content isdetermined by the Lowry's method (Lowry et al., J. Biol. Chem., 1953).The membrane suspension is stored at -70° C. in 50.0 mM Tris HCl,containing 0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 mlcontaining 10.0 mg protein per ml of suspension until use in subsequentbinding experiments.

For binding experiments, the following is added in μl volume to wells ofa 96 well format of a microtiter plate: 100.0 μl of 100.0 mM Tris.HClbuffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl₂ and a mixtureof protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF, 20.0 μl of [³ H]Arginine⁸, vasopressin (S.A. 75.0 Ci/mmole) at 0.8nM and the reaction initiated by the addition of 80.0 μl of tissuemembranes (200.0 μg tissue protein). The plates are left undisturbed onthe bench top for 120 min to reach equilibrium. Non-specific binding isassessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μlvolume. For test compounds, these are solubilized in 50%dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a finalincubation volume of 200 μl. Upon completion of binding, the content ofeach well is filtered off, using a Brandel® cell Harvester(Gaithersburg, Md.). The radioactivity trapped on the filter disk by theligand-receptor complex is assessed by liquid scintillation counting ina Packard LS Counter, with an efficiency of 65% for tritium. The dataare analyzed for IC₅₀ values by the LUNDON-2 program for competition(LUNDON SOFTWARE, Ohio). The results of this test on representativecompounds of this invention are shown in Table XIII.

Radioligand Binding Experiments with Human Platelet Membranes

(a) Platelet Membrane Preparation:

Frozen platelet rich plasma (PRP), (Platelet Source: Hudson Valley BloodServices, Westchester Medical Center, Valhalla, N.Y.) are thawed to roomtemperature. The tubes containing the PRP are centrifuged at 16,000× gfor 10 min. at 4° C. and the supernatant fluid discarded. The plateletsresuspended in an equal volume of 50.0 mM Tris.HCl, pH 7.5 containing120 mM NaCl and 20.0 mM EDTA. The suspension is recentrifuged at 16,000×g for 10 min. This washing step is repeated one more time. The washdiscarded and the lysed pellets homogenized in low ionic strength bufferof Tris.HCl, 5.0 mM, pH 7.5 containing 5.0 mM EDTA. The homogenate iscentrifuged at 39,000× g for 10 min. The resulting pellet is resuspendedin Tris. HCl buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000× g for10 min. The final pellet is resuspended in 50.0 mM Tris. HCl buffer pH7.4 containing 120 mM NaCl and 5.0 mM KCl to give 1.0-2.0 mg protein perml of suspension.

(b)Binding to Vasopressin V₁ receptor subtype in Human

Platelet Membranes

In wells of a 96 well format microtiter plate, add 100 μl of 50.0 mMTris.HCl buffer containing 0.2% BSA and a mixture of protease inhibitors(aprotinin, leupeptin etc.). Then add 20 μl of [³ H]Ligand (Manning orArg⁸ Vasopressin), to give final concentrations ranging from 0.01 to10.0 nM. Initiate the binding by adding 80.0 μl of platelet suspension(approx. 100 μg protein). Mix all reagents by pipetting the mixture upand down a few times. Non specific binding is measured in the presenceof 1.0 μM of unlabeled ligand (Manning or Arg⁸ Vasopressin). Let themixture stand undisturbed at room temperature for ninety (90) min. Uponthis time, rapidly filter off the incubate under vacuum suction overGF/B filters, using a Brandel Harvester. Determine the radioactivitycaught on the filter disks by the addition of liquid scintillant andcounting in a liquid scintillator.

Binding to Membranes of Mouse Fibroblast Cell Line (LV-2) Transfectedwith the cDNA Expressing the Human V₂ Vasopressin Receptor

(a) Membrane Preparation

Flasks of 175 ml capacity, containing attached cells grown toconfluence, are cleared of culture medium by aspiration. The flaskscontaining the attached cells are rinsed with 2×5 ml of phosphatebuffered saline (PBS) and the liquid aspirated off each time. Finally, 5ml of an enzyme free dissociation Hank's based solution (SpecialtyMedia, Inc., Lafayette, N.J.) is added and the flasks are leftundisturbed for 2 min. The content of all flasks is. poured into acentrifuge tube and the cells pelleted at 300× g for 15 min. The Hank'sbased solution is aspirated off and the cells homogenized with apolytron at setting #6 for 10 sec in 10.0 mM Tris.HCl buffer, pH 7.4containing 0.25M sucrose and 1.0 mM EDTA. The homogenate is centrifugedat 1500× g for 10 min to remove ghost membranes. The supernatant fluidis centrifuged at 100,000× g for 60 min. to pellet the receptor protein.Upon completion, the pellet is resuspended in a small volume of 50.0 mMTris. HCl buffer, pH 7.4. The protein content is determined by the Lowrymethod and the receptor membranes are suspended in 50.0 mM Tris.HClbuffer containing 0.1 mM phenylmethylsulfonylfluoride (PMSF) and 0.2%bovine serum albumin (BSA) to give 2.5 mg receptor protein per ml ofsuspension.

(b) Receptor Binding

For binding experiments, the following is added in μl volume to wells ofa 96 well format of a microtiter plate: 100.0 μl of 100.0 mM Tris.HClbuffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl₂ and a mixtureof protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF., 20.0 μl of [³ H] Arginine⁸, vasopressin (S.A. 75.0 Ci/mmole) at0.8 nM and the reaction initiated by the addition of 80.0 μl of tissuemembranes (200.0 μg tissue protein). The plates are left undisturbed onthe bench top for 120 min to reach equilibrium. Non specific binding isassessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μlvolume. For test compounds, these are solubilized in 50%dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a finalincubation volume of 200 μl. Upon completion of binding, the content ofeach well is filtered off, using a Brandel® cell Harvester(Gaithersburg, Md.). The radioactivity trapped on the filter disk by theligand-receptor complex is assessed by liquid scintillation counting ina Packard LS Counter, with an efficiency of 65% for tritium. The dataare analyzed for IC₅₀ values by the LUNDON-2 program for competition(LUNDON SOFTWARE, Ohio).

                                      TABLE XIII                                  __________________________________________________________________________    Binding Assay to Rat Hepatic V.sub.1 Receptors and Rat Kidney                 Medullary V.sub.2 Receptors or *Binding to V.sub.1 Receptor Subtype in        Human                                                                         Platelet and **Binding to Membranes of Mouse Fibroblast                       Cell Line (LV-2) Transfected with the cDNA Expressing the                     Human V.sub.2 Receptor                                                                                              V.sub.1 V.sub.2                         Ex. No.                                                                            Structure                        IC.sub.50 (μM)                                                                     IC.sub.50 (μM)               __________________________________________________________________________     1                                                                                  ##STR101##                       0.097  0.029                           215                                                                                 ##STR102##                       0.016  0.022                            3                                                                                  ##STR103##                       0.038  0.004                            4                                                                                  ##STR104##                       0.12   0.014                            5                                                                                  ##STR105##                       0.015  0.025                            6                                                                                  ##STR106##                       0.023  0.003                            7                                                                                  ##STR107##                       0.01   0.005                            8                                                                                  ##STR108##                       0.056  0.035                            14                                                                                 ##STR109##                       0.17   0.066                            40                                                                                 ##STR110##                       2.4    0.12                             41                                                                                 ##STR111##                       0.037  0.017                            82                                                                                 ##STR112##                      (10 μM)23%                                                                         (10 μM)71%                    84                                                                                 ##STR113##                       0.045  0.077                            85                                                                                 ##STR114##                       0.009  0.013                            87                                                                                 ##STR115##                      (10 μM)63%                                                                         (10 μM)80%                    89                                                                                 ##STR116##                       0.023  0.008                            91                                                                                 ##STR117##                       0.026  0.022                            93                                                                                 ##STR118##                       0.0009 0.0007                           96                                                                                 ##STR119##                       0.056  0.011                           116                                                                                 ##STR120##                       0.28   0.085                           117                                                                                 ##STR121##                       2.77   0.377                           354                                                                                 ##STR122##                       0.012  0.007                           355                                                                                 ##STR123##                       0.165  0.35                            356                                                                                 ##STR124##                       0.087  0.053                           357                                                                                 ##STR125##                       0.019  0.017                           358                                                                                 ##STR126##                       0.011  0.016                           384                                                                                 ##STR127##                       0.188  0.059                            2                                                                                  ##STR128##                       0.031  0.014                            9                                                                                  ##STR129##                       0.007  0.004                            17 160                                                                             ##STR130##                       1.2    0.11                             21                                                                                 ##STR131##                       0.93   0.087                            36 179                                                                             ##STR132##                       0.10   0.054                            54                                                                                 ##STR133##                       0.31*  0.007**                          99                                                                                 ##STR134##                       0.027  0.010                           210 214                                                                             ##STR135##                       0.058  0.016                           217                                                                                 ##STR136##                       0.068  0.19*                                                                         0.005 0.01**                    267 271                                                                             ##STR137##                       0.22   0.028                           274                                                                                 ##STR138##                       0.24*  0.031**                         297 298                                                                             ##STR139##                       0.27   0.033                           465                                                                                 ##STR140##                       0.020* 0.0015**                        466                                                                                 ##STR141##                       0.026  0.004                           467                                                                                 ##STR142##                       0.031  0.005                           468                                                                                 ##STR143##                       0.027  0.029                           469                                                                                 ##STR144##                       0.094  0.015                           470                                                                                 ##STR145##                       0.054  0.0045                          471                                                                                 ##STR146##                       0.045  0.0083                          472                                                                                 ##STR147##                       0.89   (10 μM)22%                   473                                                                                 ##STR148##                      (10 μM)90%                                                                         (10 μM)56%                   474                                                                                 ##STR149##                       0.087  0.038                           476                                                                                 ##STR150##                       0.084  0.069                           477                                                                                 ##STR151##                       0.003* 0.0032**                        478                                                                                 ##STR152##                       0.032* 0.0019**                        479                                                                                 ##STR153##                       0.023* 0.008                           480                                                                                 ##STR154##                       0.54*  0.026**                         481                                                                                 ##STR155##                       1.0    0.0034                          482                                                                                 ##STR156##                       0.41   0.0023                          484                                                                                 ##STR157##                       0.097  0.025                           485                                                                                 ##STR158##                       0.24   0.013                           486                                                                                 ##STR159##                      (10 μM)39%                                                                         (10 μM)77%                   488                                                                                 ##STR160##                      (10 μM)96%                                                                         (10 μM)87%                   489                                                                                 ##STR161##                      (10 μM)61%                                                                         (10 μM)82%                   490                                                                                 ##STR162##                       0.014  0.005                           491                                                                                 ##STR163##                      (10 μM)82%                                                                         (10 μM)83%                   492                                                                                 ##STR164##                       0.16   3.2                             493                                                                                 ##STR165##                       0.14   (10 μM)68%                   494                                                                                 ##STR166##                       0.11   5.8                             517                                                                                 ##STR167##                       0.21   0.015                           518                                                                                 ##STR168##                       0.22*  0.0017**                        519                                                                                 ##STR169##                       0.12*  0.0032**                        520                                                                                 ##STR170##                       0.85*  0.0044**                        523                                                                                 ##STR171##                       0.11*  0.0028**                        524                                                                                 ##STR172##                       0.17*  0.0012**                        525                                                                                 ##STR173##                       0.43*  0.00042**                       526                                                                                 ##STR174##                       0.05*  0.0033**                        527                                                                                 ##STR175##                       0.026* 0.00067**                       528                                                                                 ##STR176##                       0.20*  0.006**                         538                                                                                 ##STR177##                       0.052* 0.001**                         546                                                                                 ##STR178##                       0.066* 0.073**                         547                                                                                 ##STR179##                       0.016* 0.004**                         529                                                                                 ##STR180##                       0.99*  0.002**                         530                                                                                 ##STR181##                       0.003* 0.0037                          580                                                                                 ##STR182##                       0.2    0.08                            581                                                                                 ##STR183##                       0.021  0.0053                          582                                                                                 ##STR184##                       0.13   0.014                           583                                                                                 ##STR185##                       0.054  0.027                           584                                                                                 ##STR186##                       1.2    0.48                            585                                                                                 ##STR187##                       0.28   0.083                           586                                                                                 ##STR188##                       0.45   0.23                            587                                                                                 ##STR189##                       0.067  0.022                           588                                                                                 ##STR190##                       0.040  0.012                           589                                                                                 ##STR191##                      (10 μM)91%                                                                         (10 μM)82%                   590                                                                                 ##STR192##                      (10 μM)89%                                                                         (10 μM)81%                   591                                                                                 ##STR193##                      (10 μM)45%                                                                         (10 μM)64%                   592                                                                                 ##STR194##                       3.3    0.24                            593                                                                                 ##STR195##                       0.21   0.042                           594                                                                                 ##STR196##                      (10 μM)78%                                                                         (10 μM)23%                   595                                                                                 ##STR197##                      (10 μM)57%                                                                         (10 μM)93%                   687                                                                                 ##STR198##                       0.002* 0.007**                         597                                                                                 ##STR199##                      (10 μM)100%                                                                        (10 μM)97%                   598                                                                                 ##STR200##                      (10 μM)58%                                                                         (10 μM)93%                   599                                                                                 ##STR201##                       0.046  0.014                           600                                                                                 ##STR202##                       0.42   0.74                            609                                                                                 ##STR203##                       2.4*   0.021**                         611                                                                                 ##STR204##                       0.5*   0.004**                         660                                                                                 ##STR205##                       0.073  0.064                           661                                                                                 ##STR206##                       0.057  0.057                           662                                                                                 ##STR207##                       0.04   0.035                           663                                                                                 ##STR208##                       0.009  0.025                           664                                                                                 ##STR209##                       0.12   0.048                           665                                                                                 ##STR210##                       0.056  0.039                           666                                                                                 ##STR211##                       0.16   0.013                           667                                                                                 ##STR212##                       0.17   0.013                           668                                                                                 ##STR213##                       0.17*  0.029**                         669                                                                                 ##STR214##                       0.071* 0.035**                         689                                                                                 ##STR215##                       0.085* 0.54**                          676                                                                                 ##STR216##                      (10 μM)41%                                                                         (10 μM)89%                   670                                                                                 ##STR217##                       1.1    0.29                            685                                                                                 ##STR218##                       0.061* 0.061**                         612                                                                                 ##STR219##                       1.7*   0.01**                          688                                                                                 ##STR220##                       0.069* 0.034**                         690                                                                                 ##STR221##                       0.22*  0.022**                         691                                                                                 ##STR222##                       0.072* 0.0029**                        692                                                                                 ##STR223##                       0.007* 0.004**                         693                                                                                 ##STR224##                       0.021* 0.005**                         694                                                                                 ##STR225##                       0.12   0.0017**                        695                                                                                 ##STR226##                       0.015* 0.0018**                        696                                                                                 ##STR227##                      12.4*   0.065**                         697                                                                                 ##STR228##                       0.62*  0.003**                         698                                                                                 ##STR229##                       1.3*   0.013**                         699                                                                                 ##STR230##                      (1 μM)19%                                                                          (1 μM)100%                   700                                                                                 ##STR231##                      (1 μM)77%*                                                                         (10 μM)100%**                701                                                                                 ##STR232##                       0.34*  (1 μM)100%                   702                                                                                 ##STR233##                      (1 μM)9%*                                                                          (1 μM)85%**                  703                                                                                 ##STR234##                      (1 μM)35%*                                                                         (1 μM)87%**                  704                                                                                 ##STR235##                      (1 μM)100%*                                                                        (1 μM)92%**                  707                                                                                 ##STR236##                       0.20*  0.006**                         714                                                                                 ##STR237##                       0.023* 0.041**                         715                                                                                 ##STR238##                       0.0078*                                                                              0.073**                         716                                                                                 ##STR239##                       0.002* 0.031**                         __________________________________________________________________________

Vasopressin V₂ Antagonist Activity in Conscious Hydrated Rats

Conscious hydrated rats are treated with compounds under study from 0.1to 100 mg/kg orally or vehicle. Two to four rats are used for eachcompound. One hour later, arginine vasopressin (AVP, antidiuretichormore, ADH) dissolved in peanut oil is administered at 0.4 μg/kgintraperitoneally. Two rats in each test would not receive argininevasopressin but only the vehicle (peanut oil) to serve as water-loadingcontrol. Twenty minutes later each rat is given 30 mL/kg of deionizedwater orally by gavage and is placed individually in a metabolic cageequipped with a funnel and a graduated glass cylinder to collect urinefor four hours. Urine volume is measured and osmolality analyzed by useof a Fiske One-Ten osmometer (Fiske Assoc., Norwood, Mass., USA).Urinary sodium, potassium, and chloride are analyzed by use ofion-specific electrodes in a Beckman E3 (Electrolyte 3) Analyzer.

In the following results, decreased urine volume and decreasedosmolality relative to AVP-control indicates activity. The results ofthis test on representative compounds of this invention are shown inTable XIV.

                  TABLE XIV                                                       ______________________________________                                        Vasopressin V.sub.2 Antagonist Activity In                                    Conscious Hydrated Rats                                                               Dose             Urine Volume                                                                            Osmolality                                 Ex. No. (mg/kg)  N       (ml/4 hrs)                                                                              (mOsm/kg)                                  ______________________________________                                        *                78      13.3 ± 0.3                                                                           229 ± 6                                 **               6       12.1 ± 1                                                                             497 ± 53                                                 4       12.4 ± 0.8                                                                           361 ± 30                                ***              76        2 ± 0.2                                                                            1226 ± 58                               1       30       2        1.1      1504                                       215     30       2        0.7      1520                                       3       10       7       15.8 ± 1                                                                             567 ± 33                                         3       8        9.6 ± 0.9                                                                           584 ± 56                                         1       5        6.5 ± 1                                                                             515 ± 79                                4       10       2       16.9      571                                                 3       4        9.5 ± 1.2                                                                            646 ± 115                                       1       2         2       1129                                       5       30       2        7.7       955                                               10       2        8.5      1079                                       6       30       5       17.9 ± 1.3                                                                           616 ± 87                                        10       8       20.4 ± 1.1                                                                           346 ± 25                                         3       4       15 ± 1.6                                                                             519 ± 30                                         1       2        6         970                                       7       30       2       12.4       815                                               10       2        9         780                                       8       30       2        9.1      1010                                               10       2        3.4      1211                                       14      10       2        5.2       836                                                3       2        4.5      1000                                       82      30       2        1.7      1808                                               30       2        6.5       425                                               10       2        4.4       416                                               30       2       12.5       383                                               10       2        2        1123                                               20       2        4.3      1300                                               10       2        3        1488                                               30       2        3.3      1320                                               10       2       12.5       414                                                3       2        2.3      1267                                               30       2        5.1       594                                               10       4       10.3 ± 1.3                                                                           647 ± 63                                         3       2        4.4       716                                       16      30       2        8        1295                                               10       2        5.5      1242                                       354     10       2        8.8      1010                                       356     10       2        5.8      1023                                       358     30       2        5.5       875                                       2       10       2        9.3      1015                                       9       10       2        5.8       702                                       99      30       2       15.2       334                                       467     10       2       18         365                                       466     10       2       14.1       522                                       17, 160 30       2        4.1      1374                                       489     10       2        6.1      1194                                       490     10       4       71.5 ± 1.6                                                                           487 ± 38                                590     10       2        3        1355                                       581     10       4        4 ± 1.2                                                                              941 ± 219                              469     10       2       11.3       548                                       599     10       2       18         407                                       470     10       3       17         387                                       484     10       2        8         785                                       485     10       2        4         961                                       471     10       4       14.1 ± 1.9                                                                           507 ± 38                                479     10       2        6        1042                                       482     10       4       22 ± 0.9                                                                             372 ± 17                                54      10       2        5        1275                                       274     10       2        3        1177                                       465     10       2       21.8       361                                       480     10       2        8.8       827                                       528     10       2       11.3       647                                       529     10       2       10.5       569                                       520     10       2       18.5       394                                       519     10       2       19.9       399                                       523     10       2        5        1218                                       524     10       2       10         528                                       525     10       2       13         557                                       526     10       2       17.8       455                                       527     10       2       19.5       430                                       530     10       2        6         914                                       518     10       2       17.5       363                                       668     10       2       20.7       378                                       609                                                                           611                                                                           472     10       2        4.3      1453                                       582     10       2        9.5       604                                       473     10       2        2.3      1493                                       474     10       2       11.5       619                                       594     10       4        4.9 ± 1.2                                                                           1172 ± 182                              586     10       2        4.3      1196                                       584     10       2        2.5      1718                                       595     10       2        8.3      1474                                       588     10       2        9.5       687                                       587     10       2        9         868                                       210, 214                                                                              10       2       15.2       451                                       597     10       2        5.3      1250                                       517     10       2       14.7       411                                       217     10       2       14.3       466                                       585     10       2        3.3      1483                                       476     10       2        5        1233                                       593     10       2       11.8       577                                       596     10       2        2.8      1347                                       297(298)                                                                              10       2        7         796                                       477     10       2        5.3       701                                       478     10       2        3        1399                                       481     10       3       17.2       473                                       267, 271                                                                      592                                                                           ______________________________________                                         *Water-load control                                                           **Waterload                                                                   Control + DMSO (10%)                                                          (20%)                                                                         ***AVPcontrol                                                            

Vasopressin V₁ Antagonist Activity in Conscious Rats

Conscious rats are restrained in a supine position with elastic tape.The area at the base of the tail is locally anesthetized by subcutaneousinfiltration with 2% procaine (0.2 ml). Using aseptic technique theventral caudal tail artery is isolated and a cannula made of PE 10 and20 (heat-fused) tubing is passed into the lower abdominal aorta. Thecannula is secured, heparinized (1000 i.u./cc), sealed and the woundclosed with one or two stitches of Dexon 4-0. The caudal vein is alsocannulated in the same manner for intravenous drug administration. Theduration of the surgery is approximately 5 minutes. Additional localanesthesia (2% procaine or lidocaine) is provided as needed.

The animals are placed in plastic restraining cages in an uprightposition. The cannula is attached to a Statham P23Db pressure transducerand pulsatile blood pressure is recorded. Increase of systolic bloodpressure responses to arginine vasopressin 0.01 and 0.2 internationalunit (I.U.)(350 I.U.=1 mg) injections are recorded prior to any drug(compound) administration, after which each rat is dosed orally withcompounds under study 0.1-100 mg/kg (10 cc/kg) or intravenously 0.1-30mg/kg (1 cc/kg). The vasopressin injections are repeated30,60,90,120,180,240 and 300 min. later. Percentage of antagonism by thecompound is calculated using the pre-drug vasopressin vasopressorresponse as 100%.

The results of this test on representative compounds of this inventionare shown in Table XV.

The results of this test on representative compounds of this inventionin which the dose, the maximum % inhibition and the time in minutes, areshown in Table XVI.

                                      TABLE XV                                    __________________________________________________________________________    VASOPRESSIN (VAS) VASOPRESSOR RESPONSE                                                    VAS Dose                                                                 Dose i.u./kg                                                                             Min Post                                                                           Control                                                                              Response   Average                                                                            %                                      (mg/kg)                                                                            I.V.  Dose Before VAS                                                                           After VAS                                                                           Change                                                                             Change                                                                             Inhibition                      __________________________________________________________________________    CONTROL     0.01   0   155    188   33   3.5                                                         156    190   34                                                    0.02       153    213   60   52.5                                                        165    210   45                                        Ex. No. 1                                                                            10 i.v.                                                                            0.01   30  161    165   4    4    88                                          0.02       170    174    4                                                               159    170   11   8    85                                                     167    172    5                                                    0.01   60  157    173   16   16.5 51                                                     164    181   17                                                    0.02       157    182   25   20   62                                                     178    193   15                                                    0.01   90  151    176   25   21   37                                                     159    176   17                                                    0.02       154    184   30   27   49                                                     165    189   24                                                    0.01  120  150    173   23   22.5 33                                                     157    179   22                                                    0.02       150    191   41   37.5 29                                                     162    196   34                                                    0.01  180  148    177   29   29   13                                                     155    184   29                                                    0.02       151    209   58   48    9                                                     165    203   38                                                    0.01  240  146    176   30   27   19                                                     151    175   24                                                    0.02       151    200   49   39.5 25                                                     162    192   30                                                    0.01  300  146    176   30   32    4                                                     151    185   34                                                    0.02       151    200   49   39.5 25                                                     162    192   30                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,480                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   131    168   37   31                                                          167    192   25                                                    0.02       131    190   59   50                                                          173    214   41                                        Ex. No. 2                                                                            10 i.v.                                                                            0.01   30  127    135    8   6.5  79                                                     175    180    5                                                    0.02       135    144    9   8    84                                                     178    185    7                                                    0.01   60  137    144    7   8    74                                                     172    181    9                                                    0.02       135    145   10   13   74                                                     176    192   16                                                    0.01   90  124    138   14   10.5 66                                                     173    180    7                                                    0.02       132    147   15   15   70                                                     173    188   15                                                    0.01  120  135    143    8   9.5  69                                                     167    178   11                                                    0.02       134    150   16   15   70                                                     170    184   14                                                    0.01  180  124    142   18   14   55                                                     165    175   10                                                    0.02       129    150   21   22   56                                                     162    185   23                                                    0.01  240  125    144   19   16.5 47                                                     164    178   14                                                    0.02       133    158   25   25   50                                                     167    192   25                                                    0.01  300  127    145   18   17.5 44                                                     159    176   17                                                    0.02       134    170   36   31.5 37                                                     163    190   27                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 430,480                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   175    215   40   50                                                          175    235   60                                                    0.02       185    240   55   55                                                          200    255   55                                        Ex. No. 3                                                                            3 i.v.                                                                             0.01   30  180    190   10   15   70                                                     175    195   20                                                    0.02       180    205   25   23.5 57                                                     185    207   22                                                    0.01   60  185    190    5   12.5 75                                                     180    200   20                                                    0.02       185    195   10   17.5 68                                                     185    210   25                                                    0.01   90  175    185   10   17.5 65                                                     175    200   25                                                    0.02       185    195   10   15   73                                                     185    205   20                                                    0.01  120  170    185   15   20   60                                                     175    200   25                                                    0.02       175    200   25   32.5 41                                                     185    225   40                                                    0.01  180  175    195   20   30   40                                                     165    205   40                                                    0.02       180    235   55   55    0                                                     185    240   55                                                    0.01  240  165    195   30   40   20                                                     160    210   50                                                    0.02       180    225   45   52.5  5                                                     185    245   60                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340,330                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   170    215   45   53.5                                                        163    225   62                                                    0.02       185    225   40   52.5                                                        190    255   65                                        Ex. No. 3                                                                            30 p.o.                                                                            0.01  30   170    180   10   15   72                                                     155    175   20                                                    0.02       175    190   15   20   62                                                     160    185   25                                                    0.01   60  165    190   25   22.5 57                                                     150    170   20                                                    0.02       170    190   20   22.5 57                                                     160    185   25                                                    0.01   90  165    175   10   10   81                                                     160    170   10                                                    0.02       165    185   20   20   62                                                     160    180   20                                                    0.01  120  160    175   15   10   81                                                     165    170    5                                                    0.02       165    170    5   12.5 76                                                     165    185   20                                                    0.01  180  175    180    5   10   81                                                     170    185   15                                                    0.02       170    185   15   17.5 67                                                     165    185   20                                                    0.01  240  170    175    5   5    91                                                     160    165    5                                                    0.02       165    170    5   10   81                                                     160    175   15                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340,340                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   155    215   60   57.5                                                        165    220   55                                                    0.02       190    230   40   50                                                          175    235   60                                        Ex. No. 3                                                                            10 p.o.                                                                            0.01   30  150    165   15   12.5 78                                                     175    185   10                                                    0.02       155    175   20   17.5 65                                                     175    190   15                                                    0.01   60  150    160   10   17.5 70                                                     155    180   25                                                    0.02       155    180   25   22.5 55                                                     160    180   20                                                    0.01   90  145    170   20   65   81                                                     160    175   15                                                    0.02       155    205   50   40   20                                                     155    185   30                                                    0.01  120  150    165   15   15   74                                                     160    175   15                                                    0.02       155    210   55   45   10                                                     160    195   35                                                    0.01  180  145    165   20   20   65                                                     155    175   20                                                    0.02       150    190   40   35   30                                                     165    195   30                                                    0.01  240  145    165   20   22.5 61                                                     160    185   25                                                    0.02       155    200   45   47.5  5                                                     165    215   50                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340,360                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   167    209   42   35                                                          170    198   28                                                    0.02       170    232   62   54.5                                                        177    224   47                                        Ex. No. 3                                                                            10 p.o.                                                                            0.01   30  116    124    8   10   71                                                     172    184   12                                                    0.02       113    128   15   18.5 66                                                     168    190   22                                                    0.01   60  115    122    7   10.5 70                                                     170    184   14                                                    0.02       116    133   17   18.5 66                                                     168    188   20                                                    0.01   90  116    122    6   6.5  81                                                     134    141    7                                                    0.02       160    185   25   24   56                                                     167    190   23                                                    0.01  120  162    172   10   14.5 59                                                     165    184   19                                                    0.02       160    168    8   10.5 81                                                     161    174   13                                                    0.01  180  162    162    0   8    77                                                     164    180   16                                                    0.02       156    165    9   13.5 75                                                     163    181   18                                                    0.01  240  162    168    6   8.5  76                                                     170    181   11                                                    0.02       160    170   10   22.5 59                                                     175    210   35                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 380,360                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   147    182   35   40                                                          136    181   45                                                    0.02       150    213   63   54                                                          146    191   45                                        Ex. No. 3                                                                            10 p.o.                                                                            0.01   30  147    157   10   11   73                                                     132    144   12                                                    0.02  148  162    14    16   70                                                          134    152   18                                                    0.01   60  143    155   12   11.5 71                                                     136    147   11                                                    0.02       151    160    9   22.5 58                                                     134    154   12   12   70                                          0.01   90  142    154   12   12   70                                                     133    145   12                                                    0.02       145    162   17   17.5 68                                                     130    148   18                                                    0.01  120  139    154   15   12.5 69                                                     133    143   10                                                    0.02       136    164   28   22.5 58                                                     127    144   17                                                    0.01  180  147    160   13   15.5 61                                                     120    138   18                                                    0.02       144    168   24   25   54                                                     122    148   26                                                    0.01  240  145    163   18   19.5 51                                                     122    143   21                                                    0.02       144    188   44   35.5 34                                                     126    153   27                                                    0.01  300  146    166   20   16.5 59                                                     124    137   13                                                    0.02       153    180   27   24   56                                                     134    155   21                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,390                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   146    200   54   49                                                          139    183   44                                                    0.02       148    205   57   51.5                                                        146    192   46                                        Ex. No. 3                                                                             3 i.v.                                                                            0.01   30  143    158   15   15   69                                                     124    139   15                                                    0.02       145    166   21   22   57                                                     160    183   23                                                    0.01   60  143    161   18   21   57                                                     131    155   24                                                    0.02       147    185   38   29   44                                                     138    158   20                                                    0.01   90  128    148   20   12   76                                                     148    152    4                                                    0.02       154    188   34   28   46                                                     133    155   22                                                    0.01  120  137    155   18   20.5 58                                                     148    171   23                                                    0.02       138    161   23   18.5 64                                                     148    162   14                                                    0.01  180  146    162   16   21   57                                                     139    165   26                                                    0.02       148    179   31   28.5 45                                                     146    172   26                                                    0.01  240  142    166   24   32   35                                                     132    172   40                                                    0.02       126    145   19   27.5 47                                                     139    175   36                                                    0.01  300  141    162   21   19   61                                                     146    163   17                                                    0.02       146    179   33   30.5 41                                                     145    173   28                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 510,510                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   140    175   35   47.5                                                        142    202   60                                                    0.02       155    194   39   49.5                                                        154    214   60                                        Ex. No. 4                                                                            10 p.o.                                                                            0.01   30  133    173   40   44.5  6                                                     139    188   49                                                    0.02       154    178   24   36   27                                                     153    201   48                                                    0.01   60  156    177   212  30.5 36                                                     142    182   40                                                    0.02       156    182   26   44.5 10                                                     145    208   63                                                    0.01   90  153    180   27   38.5 19                                                     141    191   50                                                    0.02       163    199   36   52   -5                                                     152    220   68                                                    0.01  120  164    198   34   32.5 32                                                     146    177   31                                                    0.02       161    194   33   50.5 -2                                                     146    214   68                                                    0.01  180  149    183   34   35.5 25                                                     141    178   37                                                    0.02       148    185   37   44   11                                                     141    192   51                                                    0.01  240  148    169   21   29   39                                                     133    170   37                                                    0.02       1548   184   26   26   47                              __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,510                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   137    170   33   31.5                                                        139    169   30                                                    0.02       141    193   52   48                                                          122    166   44                                        Ex. No. 5                                                                            10 i.v.                                                                            0.01   30  141    146    5   5.5  83                                                     120    126    6                                                    0.02       143    155   12   13.5 72                                                     137    152   15                                                    0.01   60  144    152    8   7.5  76                                                     123    130    7                                                    0.02       144    155   11   10.5 78                                                     124    134   10                                                    0.01 90                                                                             148  155     7    9    71                                                          141    152   11                                                    0.02       146    155    9   8    83                                                     145    152    7                                                    0.01  120  144    158   14   13   59                                                     123    135   12                                                    0.02       148    164   16   15   69                                                     126    140   14                                                    0.01  180  143    156   13   12   62                                                     124    135   11                                                    0.02       145    164   19   19   60                                                     123    142   19                                                    0.01  240  137    155   18   17   46                                                     117    133   16                                                    0.02       135    160   25   23.5 51                                                     118    140   22                                                    0.01  300  130    161   31   30    5                                                     112    141   29                                                    0.02       139    181   42   39.5 18                                                     119    156   37                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,410                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   143    189   46   36.5                                                        162    189   27                                                    0.02       151    195   44   42                                                          162    202   40                                        Ex. No. 6                                                                            10 i.v.                                                                            0.01   30  152    158    6   5.5  85                                                     157    162    5                                                    0.02       144    165   21   16   62                                                     147    158   11                                                    0.01   60  150    163   13   7.5  79                                                     177    179    2                                                    0.02       144    170   26   23   45                                                     162    182   20                                                    0.01   90  139    153   14   13.5 63                                                     155    168   13                                                    0.02  145  168    23    27   36                                                          154    185   31                                                    0.01  120  143    160   17   15   59                                                     154    167   13                                                    0.02       143    176   33   29.5 30                                                     151    177   26                                                    0.01  180  138    165   27   20.5 44                                                     152    166   14                                                    0.02       148    189   41   35   17                                                     157    186   29                                                    0.01  240  143    175   32   24   34                                                     163    179   16                                                    0.02       151    199   48   35.5 15                                                     166    189   23                                                    0.01  300  143    175   32   25.5 30                                                     165    184   19                                                    0.02       152    193   41   36   14                                                     173    204   31                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 480,520                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   144    181   37   47                                                          134    191   57                                                    0.02       140    190   50   56                                                          150    212   62                                        Ex. No. 7                                                                            10 i.v.                                                                            0.01   30  141    151   10   6    87                                                     152    154    2                                                    0.02       147    162   15   7.5  87                                                     159    159    0                                                    0.01   60  138    143    5   6    87                                                     148    155    7                                                    0.02       136    145    9   8    86                                                     148    155    7                                                    0.01   90  134    147   13   8.5  82                                                     142    146    4                                                    0.02       137    149   12   12.5 78                                                     139    152   13                                                    0.01  120  132    142   10   9.5  80                                                     136    145    9                                                    0.02       134    150   16   13   77                                                     141    151   10                                                    0.01  180  136    151   15   17.5 63                                                     138    158   20                                                    0.02       136    158   22   23   59                                                     134    158   24                                                    0.01  240  129    146   17   20.5 56                                                     132    156   24                                                    0.02       131    157   26   30.5 46                                                     143    178   35                                                    0.01  300  128    146   18   20   57                                                     136    158   22                                                    0.02       134    151   17   23   59                                                     145    174   29                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 550,530                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   142    191   49   37                                                          145    170   25                                                    0.02       152    213   61   51.5                                                        147    189   42                                        Ex. No. 8                                                                            10 i.v.                                                                            0.01   30  156    178   22   14.5 61                                                     145    152    7                                                    0.02       150    176   26   23.5 54                                                     139    160   21                                                    0.01   60  145    154    9   14.5 61                                                     150    170   20                                                    0.02       145    162   17   21.5 58                                                     158    184   26                                                    0.01   90  146    154    8   10   73                                                     160    172   12                                                    0.02       142    160   18   17.5 66                                                     161    178   17                                                    0.01  120  141    154   13   11.5 69                                                     156    166   10                                                    0.02       139    154   15   15.5 70                                                     162    178   16                                                    0.01  180  139    156   17   14   62                                                     157    168   11                                                    0.02       140    172   32   28   46                                                     158    182   24                                                    0.01  240  138    151   13   15   59                                                     148    165   17                                                    0.02       143    178   35   29   44                                                     152    175   23                                                    0.01  300  143    161   18   18   51                                                     147    165   18                                                    0.02       153    183   30   28   46                                                     157    183   26                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 585,450                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   167    183   16   22                                                          162    190   28                                                    0.02       163    193   30   50.5                                                        154    225   71                                        Ex. No. 41                                                                           10 i.v.                                                                            0.01   30  153    164   11   12   45                                                     163    176   13                                                    0.02       161    194   33   23.5 53                                                     155    169   14                                                    0.01   60  161    171   10   9    59                                                     159    167    8                                                    0.02       156    172   16   18   64                                                     153    173   20                                                    0.01   90  154    169   15   14   36                                                     166    179   13                                                    0.02       151    179   28   22.5 55                                                     153    170   17                                                    0.01  120  150    160   10   14   36                                                     151    169   18                                                    0.02       149    163   14   16.5 67                                                     164    183   19                                                    0.01  180  153    167   14   13.5 39                                                     156    169   13                                                    0.02       154    172   18   21   58                                                     155    179   24                                                    0.01  240  151    162   11   12.5 43                                                     151    165   14                                                    0.02       156    179   23   23.5 53                                                     158    182   24                                                    0.01  300  145    160   15   15   32                                                     150    165   15                                                    0.02       150    180   30   27   47                                                     155    179   24                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,400                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   164    209   45   47.5                                                        160    210   50                                                    0.02       186    229   43   51.5                                                        156    216   60                                        Ex. No. 82                                                                           10 i.v.                                                                            0.01   30  156    195   39   36   24                                                     152    185   33                                                    0.02       165    218   53   54   -5                                                     159    214   55                                        Ex. No. 82                                                                           20 i.v.                                                                            0.01   60  162    180   18   15.5 67                                                     147    160   13                                                    0.02       161    199   38   37   28                                                     151    187   36                                                    0.01   90  158    181   23   23.5 51                                                     144    168   24                                                    0.02       144    175   31   24   53                                                     143    160   17                                                    0.01  120  157    173   16   16.5 65                                                     143    160   17                                                    0.02       161    200   39   38.5 25                                                     152    190   38                                                    0.01  180  149    171   22   18.5 61                                                     139    154   15                                                    0.02       150    197   47   43.5 16                                                     130    170   40                                                    0.01  240  144    175   31   29   39                                                     143    170   27                                                    0.02       150    198   48   42   18                                                     146    182   36                                                    0.01  300  152    185   33   32   33                                                     136    167   31                                                    0.02       156    206   50   53   -3                                                     147    203   56                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,470                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   147    191   44   46                                                          163    211   48                                                    0.02       154    212   58   61                                                          160    224   64                                        Ex. No. 84                                                                           10 i.v.                                                                            0.01   30  146    165   19   10.5 77                                                     172    174    2                                                    0.02       152    168   16   14.5 76                                                     159    172   13                                                    0.01   60  152    167   15   16.5 64                                                     154    172   18                                                    0.02       158    201   43   33.5 45                                                     161    185   24                                                    0.01   90  144    158   14   13   72                                                     153    165   12                                                    0.02       152    173   21   26   57                                                     156    187   31                                                    0.01  120  150    166   16   19.5 58                                                     143    166   23                                                    0.02       150    175   25   32.5 47                                                     147    187   40                                                    0.01  180  141    168   27   24.5 47                                                     149    171   22                                                    0.02       148    170   22   31.5 48                                                     148    189   41                                                    0.01  240  131    154   23   26   43                                                     143    172   29                                                    0.02       149    186   37   37   39                                                     148    185   37                                                    0.01  300  137    161   24   22.5 51                                                     151    172   21                                                    0.02       148    193   45   43   30                                                     150    191   41                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 600,490                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   144    165   21   26.5                                                        127    159   32                                                    0.02       147    190   43   35.5                                                        137    165   28                                        Ex. No. 85                                                                           10 i.v.                                                                            0.01   30  162    163    1   4.5  83                                                     119    127    8                                                    0.02       156    166   10   9    75                                                     130    138    8                                                    0.01   60  156    162    6   7    74                                                     124    132    8                                                    0.02       156    168   12   9.5  73                                                     129    136    7                                                    0.01   90  151    160    9   9.5  64                                                     125    135   10                                                    0.02       143    150    7   7.5  79                                                     124    132    8                                                    0.01  120  145    152    7   9    66                                                     123    134   11                                                    0.02       139    147    8   6.5  82                                                     127    132    5                                                    0.01  180  125    141   16   15.5 42                                                     118    133   15                                                    0.02       129    147   18   19.5 45                                                     106    127   21                                                    0.01  240  129    144   15   12   55                                                     107    116    9                                                    0.02       135    152   17   18   49                                                     108    127   19                                                    0.01  300  129    144   15   12   5                                                      107    116    9                                                    0.02       135    152   17   18   49                                                     108    127   19                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 540,530                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   141    205   64   62.5                                                        138    199   61                                                    0.02       138    227   89   66.5                                                        143    187   44                                        Ex. No. 87                                                                           10 i.v.                                                                            0.01   30  136    210   74   50   20                                                     145    171   26                                                    0.02       157    227   70   57   14                                                     144    188   44                                        Ex. No. 87                                                                           20 i.v.                                                                            0.01   60  133    150   17   14.5 77                                                     143    155   12                                                    0.02       150    191   41   32.5 51                                                     143    167   24                                                    0.01   90  140    163   23   24.5 61                                                     141    167   26                                                    0.02       148    197   49   33.5 50                                                     145    163   18                                                    0.01  120  136    162   26   26   58                                                     146    172   26                                                    0.02       152    196   44   35.5 47                                                     150    177   27                                                    0.01  180  130    163   33   26.5 58                                                     139    159   20                                                    0.02       148    192   44   37.5 44                                                     142    173   31                                                    0.01  240  135    172   37   28.5 54                                                     132    152   20                                                    0.02       136    191   55   41   38                                                     133    160   27                                                    0.01  300  140    177   37   30   52                                                     128    151   23                                                    0.02       138    201   63   48.5 27                                                     134    168   34                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 480,550                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   149    178   29   40                                                          158    209   51                                                    0.02       150    213   63   62                                                          161    222   61                                        Ex. No. 89                                                                           10 i.v.                                                                            0.01   30  155    160    5   5    88                                                     160    165    5                                                    0.02       160    170   10   5    92                                                     160    160    0                                                    0.01   60  160    170   10   7.5  81                                                     160    165    5                                                    0.02       155    170   15   10   84                                                     175    80     5                                                    0.01  90   150    155    5   7.5  81                                                     160    170   10                                                    0.02       150    165   15   12.5 80                                                     160    170   10                                                    0.01  120  140    155   15   15   63                                                     155    170   15                                                    0.02       140    170   30   27.5 56                                                     155    180   25                                                    0.01  180  135    160   25   25   38                                                     155    180   25                                                    0.02       140    170   30   32.5 48                                                     155    190   35                                                    0.01  240  135    160   25   25   38                                                     155    180   25                                                    0.02       140    170   30   35   44                                                     150    190   40                                                    0.01  300  130    155   25   27.5 31                                                     150    180   30                                                    0.02       135    170   35   32.5 48                                                     160    190   30                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 610,600                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   144    190   46   48.5                                                        154    205   51                                                    0.02       150    220   70   62.5                                                        160    215   55                                        Ex. No. 91                                                                           10 i.v.                                                                            0.01   30  145    150    5   5    90                                                     150    155    5                                                    0.02       150    160   10   7.5  88                                                     150    155    5                                                    0.01   60  157    160    3   6.5  87                                                     155    165   10                                                    0.02       150    158    8   7    89                                                     155    161    6                                                    0.01   90  155    165   10   9    81                                                     152    160    8                                                    0.02       150    165   15   12.5 80                                                     150    160   10                                                    0.01  120  150    170   20   13   73                                                     140    146    6                                                    0.02       148    165   17   17.5 72                                                     142    160   18                                                    0.01  180  142    164   22   22   55                                                     143    165   22                                                    0.02       149    167   18   29   54                                                     145    185   40                                                    0.01  240  146    165   19   20   59                                                     129    150   21                                                    0.02       147    189   42   29.5 53                                                     135    152   17                                                    0.01  300  146    164   18   16.5 66                                                     146    161   15                                                    0.02       144    167   23   32.5 48                                                     147    189   42                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 560,630                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   158    203   45   49.5                                                        154    208   54                                                    0.02       159    228   69   72                                                          160    235   75                                        Ex. No. 93                                                                           10 i.v.                                                                            0.01   30  160    162    2   2    96                                                     139    141    2                                                    0.02       157    162    5   4.5  94                                                     163    167    4                                                    0.01   60  154    154    0   3    94                                                     163    169    6                                                    0.02       161    166    5   5.5  92                                                     164    170    6                                                    0.01   90  150    155    5   5    90                                                     163    168    5                                                    0.02       154    162    8   7    90                                                     161    167    6                                                    0.01  120  151    156    5   6    88                                                     158    165    7                                                    0.02       155    160    5   7    90                                                     160    169    9                                                    0.01  180  151    161   10   13.5 73                                                     151    168   17                                                    0.02       151    164   13   15.5 78                                                     155    173   18                                                    0.01  240  145    158   13   13   74                                                     156    169   13                                                    0.02       148    166   18   17   76                                                     158    174   16                                                    0.01  300  146    158   12   12   76                                                     156    168   12                                                    0.02       144    162   18   18.5 74                                                     154    173   19                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 580,480                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   155    202   47   45.5                                                        165    209   44                                                    0.02       160    225   65   61                                                          172    229   57                                        Ex. No. 95                                                                           10 i.v.                                                                            0.01   30  163    193   30   29.5 35                                                     168    197   29                                                    0.02       170    225   55   56    8                                                     170    227   57                                        Ex. No. 95                                                                           20 i.v.                                                                            0.01   60  154    171   17   15   67                                                     156    169   13                                                    0.02       160    177   17   19.5 68                                                     162    184   22                                                    0.01   90  154    168   14   13.5 70                                                     167    180   13                                                    0.02       158    177   19   24   61                                                     164    193   29                                                    0.01  120  147    167   20   24   47                                                     161    189   28                                                    0.02       153    174   21   28.5 53                                                     161    197   36                                                    0.01  180  146    168   22   23.5 48                                                     156    181   25                                                    0.02       154    189   35   34   44                                                     161    194   33                                                    0.01  240  151    168   17   21.5 53                                                     154    180   26                                                    0.02       153    189   36   34   44                                                     165    197   32                                                    0.01  300  142    165   23   24.5 46                                                     151    177   26                                                    0.02       148    193   45   37.5 39                                                     163    193   30                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,470                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   134    163   29   32.5                                                        144    180   36                                                    0.02       137    193   56   57.5                                                        153    212   59                                        Ex. No. 95                                                                           10 i.v.                                                                            0.01   30  144    157   13   11.5 65                                                     143    153   10                                                    0.02       139    150   11   19.5 66                                                     148    176   28                                                    0.01   60  141    149    8   7    78                                                     149    155    6                                                    0.02       140    155   15   12.5 78                                                     148    158   10                                                    0.01   90  133    148   15   13.5 58                                                     148    160   12                                                    0.02       136    151   15   16   72                                                     146    163   17                                                    0.01  120  134    148   14   13.5 58                                                     146    159   13                                                    0.02       137    151   14   17.5 70                                                     148    169   21                                                    0.01  180  136    153   17   15.5 52                                                     140    154   14                                                    0.02       139    153   14   16   72                                                     136    154   18                                                    0.01  240  133    152   19   18.5 43                                                     138    156   18                                                    0.02       136    173   37   39.5 31                                                     145    187   42                                                    0.01  300  138    154   16   15.5 52                                                     137    152   15                                                               147    184   37   42   27                                                     138    185   47                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,440                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   158    181   23   29                                                          148    183   35                                                    0.02       161    198   37   48                                                          151    210   59                                        Ex. No. 116                                                                          10 i.v.                                                                            0.01   30  160    181   21   22.5 22                                                     162    186   24                                                    0.02       160    191   31   36.5 24                                                     156    198   42                                                    0.01   60  158    180   22   18   38                                                     156    170   14                                                    0.02       160    197   37   33.5 30                                                     160    190   30                                                    0.01   90  159    182   23   19   34                                                     157    172   15                                                    0.02       163    201   38   32   33                                                     162    188   26                                                    0.01  120  157    175   17   19.5 33                                                     158    179   21                                                    0.02       154    203   49   40   17                                                     167    198   31                                                    0.01  180  153    170   17   18   38                                                     157    176   19                                                    0.02       155    201   46   40   17                                                     176    210   34                                                    0.01  240  153    169   16   16   45                                                     156    172   16                                                    0.02       152    188   36   38.5 20                                                     156    197   41                                                    0.01  300  153    176   23   22   24                                                     127    148   21                                                    0.02       154    205   51   41.5 14                                                     163    195   32                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,570                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   146    184   38   36.5                                                        156    191   35                                                    0.02       146    210   64   56.5                                                        160    209   49                                        Ex. No. 117                                                                          10 i.v.                                                                            0.01   30  154    195   41   36    1                                                     162    193   31                                                    0.02       154    220   66   63   -12                                                    162    222   60                                               20 i.v.                                                                            0.01   60  154    182   28   36    1                                                     164    208   44                                                    0.02       157    197   40   40   29                                                     173    213   40                                                    0.01   90  158    174   16   22.5 38                                                     162    191   29                                                    0.02       160    208   48   46   19                                                     165    209   44                                                    0.01  120  151    171   20   23   37                                                     154    180   26                                                    0.02       150    183   33   38   33                                                     158    201   43                                                    0.01  180  141    168   27   26.5 27                                                     150    176   26                                                    0.02       143    185   42   46   19                                                     151    201   50                                                    0.01  240  139    168   29   25   32                                                     146    167   21                                                    0.02       143    175   32   40.5 28                                                     146    195   49                                                    0.01  300  137    164   27   26   29                                                     149    174   25                                                               144    183   39   42.5 25                                                     149    195   46                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 570,460                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   135    171   36   34.5                                                        121    154   33                                                    0.02       138    184   46   47.5                                                        156    205   49                                        Ex. No. 157                                                                          10 i.v.                                                                            0.01   30  136    175   39   26   25                                                     152    165   13                                                    0.02       148    199   51   38   20                                                     153    178   25                                                    0.01   60  150    179   29   26.5 23                                                     135    159   24                                                    0.02       160    191   31   31.5 34                                                     153    185   32                                                    0.01   90  145    167   22   21   39                                                     161    181   20                                                    0.02       148    185   37   40   16                                                     152    195   43                                                    0.01  120  136    161   25   26.5 23                                                     138    166   28                                                    0.02       140    183   43   39.5 17                                                     150    186   36                                                    0.01  180  131    164   33   32.5  6                                                     132    164   32                                                    0.02       137    185   48   52   -9                                                     140    196   56                                                    0.01  240  140    167   27   28.5 17                                                     155    185   30                                                    0.02       138    167   29   35.5 25                                                     143    185   42                                                    0.01  300  138    162   24   25.5 26                                                     141    168   27                                                    0.02       146    176   30   40   16                                                     156    206   50                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,470                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   146    191   45   41                                                          161    198   37                                                    0.02       157    207   50   50                                                          163    213   50                                        Ex. No. 357                                                                          10 i.v.                                                                            0.01   30  144    159   15   16.5 60                                                     167    185   18                                                    0.02       145    169   24   16   68                                                     164    172    8                                                    0.01   60  156    160    4   4.5  89                                                     164    169    5                                                    0.02       145    159   14   10.5 79                                                     164    171    7                                                    0.01   90  142    153   11   8    80                                                     167    172    5                                                    0.02       143    154   11   10.5 79                                                     168    178   10                                                    0.01  120  140    151   11   8    80                                                     165    170    5                                                    0.02       136    139    3   6    88                                                     165    174   9                                                     0.01  180  147    154    7   9.5  77                                                     162    174   12                                                    0.02       142    154   12   11   78                                                     162    172   10                                                    0.01  240  145    159   14   14   66                                                     159    173   14                                                    0.02       157    174   17   14.5 71                                                     160    172   12                                                    0.01  300  148    164   16   16   61                                                     151    167   16                                                    0.02       148    169   21   16   68                                                     158    169   11                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,460                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   139    190   51   36.5                                                        159    181   22                                                    0.02       155    212   57   39.5                                                        166    188   22                                        Ex. No. 358                                                                          10 i.v.                                                                            0.01   30  147    163   16   12   67                                                     161    169    8                                                    0.02       149    169   20   24   39                                                     162    190   28                                                    0.01   60  145    153    8   13   64                                                     153    171   18                                                    0.02       142    155   13   10   75                                                     160    167    7                                                    0.01   90  142    157   25   17.5 52                                                     156    166   10                                                    0.02       148    161   13   11   72                                                     161    170    9                                                    0.01  120  144    153    9   8    78                                                     159    166    7                                                    0.02       139    155   16   14   65                                                     155    167   12                                                    0.01  180  134    158   24   17.5 52                                                     147    158   11                                                    0.02       146    162   16   14.5 63                                                     154    167   13                                                    0.01  240  139    153   14   12   67                                                     143    153   10                                                    0.02       144    162   18   15.5 61                                                     145    158   13                                                    0.01  300  137    163   26   19   48                                                     137    149   12                                                    0.02       140    158   18   16   59                                                     141    155   14                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 520,515                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0   141    165   24   23.5                                                        145    168   23                                                    0.02       145    182   37   37                                                          153    190   37                                        Ex. No. 384                                                                          10 i.v.                                                                            0.01   30  145    157   12   9    62                                                     156    162    6                                                    0.02       150    168   18   14.5 61                                                     158    169   11                                                    0.01   60  151    160    9   9    62                                                     158    167    9                                                    0.02       152    162   10   10.5 72                                                     160    171   11                                                    0.01   90  154    170   16   12   49                                                     160    168    8                                                    0.02       157    177   20   15.5 58                                                     162    173   11                                                    0.01  120  149    159   10   10.5 55                                                     131    142   11                                                    0.02       150    162   12   11.5 69                                                     164    175   11                                                    0.01  180  150    162   12   11   53                                                     158    168   10                                                    0.02       156    167   11   13.5 64                                                     160    176   16                                                    0.01  240  145    156   11   11   53                                                     155    166   11                                                    0.02       145    161   16   15   59                                                     160    174   14                                                    0.01  300  148    162   14   12   49                                                     152    162   10                                                    0.02       151    168   17   17   54                                                     158    175   17                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 455,500                 __________________________________________________________________________    grams                                                                         CONTROL     0.01   0    96    135   39   36                                                          151    184   33                                                    0.02       131    154   23   36                                                          158    207   49                                        Ex. No. 407                                                                          10 i.v.                                                                            0.01   30  120    131   11   9.5  74                                                     150    158    8                                                    0.02       132    142   10   13   64                                                     153    169   16                                                    0.01   60  112    139   27   25.5 29                                                     150    174   24                                                    0.02       128    131    3   10   72                                                     154    171   17                                                    0.01   90   90    114   24   19   47                                                     152    166   14                                                    0.02        87    122   35   26.5 26                                                     154    172   18                                                    0.01  120  120    127    7   8.5  76                                                     145    155   10                                                    0.02       113    127   14   17   53                                                     147    167   20                                                    0.01  180  112    124   12   11.5 68                                                     141    152   11                                                    0.02       109    129   20   20   44                                                     139    159   20                                                    0.01  240  114    130   16   18   50                                                     131    151   20                                                    0.02       120    136   16   21.5 40                                                     142    169   27                                                    0.01  300  115    130   15   20   44                                                     130    155   25                                                    0.02       116    137   21   22.5 38                                                     136    160   24                                        __________________________________________________________________________    SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,550                 __________________________________________________________________________    grams                                                                     

                  TABLE XVI                                                       ______________________________________                                        VASOPRESSIN (VAS) VASOPRESSOR RESPONSE                                        Ex. No. Dose mg/kg  Max. % Inhibition                                                                          Time (min)                                   ______________________________________                                         2      30 i.v.     74           120                                           9      10 i.v.     95           60                                            17     30 i.v.     50           60                                            36     30 i.v.     71           60                                            99     10 i.v.     76           120                                          210     10 i.v.     78           90                                           217     30 i.v.     57           90                                           271     10 i.v.     56           60                                           274     10 i.v.     59           300                                          465     10 i.v.     85           90                                           466     30 i.v.     94           94                                           467     10 i.v.     65           120                                          468     10 i.v.     68           30                                           469     10 i.v.     69           30                                           470     10 i.v.     87           180                                                  30 p.o.     69           180                                          471     30 i.v.     85           90                                           472     30 i.v.     36           90                                           474     30 i.v.     80           60                                           476     10 i.v.     78           30                                                   30 p.o.     19           180                                          477     10 i.v.     88           180                                                  30 p.o.     82           30                                           478     10 i.v.     76           120                                          479     10 i.v.     83           60                                                   30 p.o.     69           90                                           480     10 i.v.     29           300                                          481     30 p.o.     58           80                                           482     10 i.v.     40           60                                           484     10 i.v.     79           300                                                  30 p.o.     22           180                                          485     30 i.v.     64           60                                           488     30 i.v.     43           60                                           489     30 i.v.     39           120                                          490     10 i.v.     74           90                                                   10 p.o.     65           120                                          517     10 i.v.     81           90                                           525     30 i.v.     70           60                                           527     30 i.v.     85           180                                          528     30 i.v.     66           300                                          530     30 i.v.     89           120                                          581     10 i.v.     94           30                                                   30 p.o.     79           30                                           582     10 i.v.     75           170                                          585     10 i.v.     56           30                                           587     10 i.v.     75           60                                           588     10 i.v.     65           90                                                   30 p.o.     80           120                                          590     30 i.v.     89           120                                          592     30 i.v.     37           90                                           593     30 i.v.     67           60                                           594     30 i.v.     36           180                                          595     30 i.v.     44           90                                           599     30 i.v.     86           90                                           600     30 i.v.     78           60                                           ______________________________________                                    

Oxytocin Receptor Binding

(a) Membrane Preparation

Female Sprague-Dawley rats weighing approximately 200-250 g are injectedintramuscularly (i.m.) with 0.3 mg/kg of body weight ofdiethylstilbestrol (DES). The rats are sacrificed 18 hours later underpentobarbital anesthesia. The uteri are dissected out, cleaned of fatand connective tissues and rinsed in 50 ml of normal saline. The tissuepooled from six rats is homogenized in 50 ml of 0.01 mM Tris.HCl,containing 0.5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4,using a polytron at setting 6 with three passes of 10 sec each. Thehomogenate is passed through two (2) layers of cheesecloth and thefiltrate centrifuged at 1000× g for 10 min. The clear supernatant isremoved and recentrifuged at 165,000× g for 30 min. The resulting pelletcontaining the oxytocin receptors is resuspended in 50.0 mM Tris.HClcontaining 5.0 mM MgCl₂ at pH 7.4, to give a protein concentration of2.5 mg/ml of tissue suspension. This preparation is used in subsequentbinding assays with [³ H]Oxytocin.

(b) Radioligand Binding

Binding of 3,5-[³ H]Oxytocin ([³ H]OT) to its receptors is done inmicrotiter plates using [³ H]OT, at various concentrations, in an assaybuffer of 50.0 mM Tris.HCl, pH 7.4 and containing 5.0 mM MgCl₂, and amixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg;1,10-phenanthroline, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100ml of buffer solution. Non-specific binding is determined in thepresence of 1.0 uM unlabeled OT. The binding reaction is terminatedafter 60 min , at 22° C. by rapid filtration through glass fiber filtersusing a Brandel® cell harvester (Biomedical Research and DevelopmentLaboratories, Inc., Gaithersburg, Md.). Competition experiments areconducted at equilibrium using 1.0 nM [³ H]OT and varying theconcentration of the displacing agents. The concentrations of agentdisplacing 50% of [³ H]OT at its sites (IC₅₀) are calculated by acomputer assisted LUNDON-2 program (LUNDON SOFTWARE INC., Ohio, USA).

The results of this assay on representative examples are shown in TableXVII.

                  TABLE XVII                                                      ______________________________________                                        Oxytocin                                                                                Dose        % Inhibition                                            Ex. No.   (μM)     at 10 μM                                                                              IC.sub.50                                    ______________________________________                                         3        10          90         0.36                                          4        10          98         0.66                                          6        10          92         0.35                                          7        10          97         0.13                                          17       10          31                                                       36       10          67         2.45                                          54       10          94         0.16                                          85       10          98         0.46                                          93       10          87         0.06                                          96       10          94         1.2                                          160       10          31                                                      164       10          67         2.45                                         210       10          64         4                                            214       10          64         4                                            215       10          74         0.57                                         217       10          87         1.2                                          274       10          95         1                                            297       10          76         4                                            298       10          76         4                                            416       10          44.6       7.4                                          417       10          21                                                      418       10          39                                                      419       10          28                                                      420       10          16                                                      429       10          11                                                      430       10          16                                                      431       10          18                                                      432       10          19                                                      433       10          12                                                      435       10          10                                                      436       10          32                                                      441       1           22                                                      443       10          70                                                      444       10          21                                                      448       10          11                                                      449       10          14                                                      450       10          22                                                      451       10          43                                                      452       10          36                                                      455       10          75         2.9                                          460       10          77         3.1                                          461       10          44.6       7.4                                          462       10          14                                                      463       10          55         8.5                                          464       10          71         2.4                                          465       10          93         0.033                                        468       10          96         0.26                                         469       10          96         0.265                                        470       2.5         92         0.22                                         471       10          99         0.35                                         472       10          0                                                       473       10          20                                                      474       10          18                                                      476       10          94         0.82                                         477       1.25        97         0.029                                        478       1.25        97         0.04                                         479       10          76         0.15                                         480       10          98         0.15                                         481       10          88         0.24                                         482       10          97         0.126                                        485       10          86         2.2                                          486       10          18                                                      489       10          44                                                      490       10          99         0.3                                          491       10          46                                                      517       10          91         0.32                                         519       10          97         0.48                                         520       10          79         2.2                                          524       10          84         1.8                                          525       10          98         0.28                                         526       10          97         0.47                                         527       10          92         0.45                                         528       10          90         1.17                                         529       10          92         0.45                                         530       10          99         0.31                                         538       10          90         0.9                                          546       10          91         0.99                                         547       5           97         0.26                                         580       10          79         2.96                                         581       10          99         0.2                                          582       10          96         0.675                                        583       10          61         4                                            584       10          26                                                      585       10          70         4.7                                          586       10          61         4.7                                          587       10          56         8                                            588       10          90         2                                            589       10          79         2.9                                          590       10          12                                                      591       10          29                                                      592       10          41                                                      593       10          82         1.1                                          594       10          19                                                      595       10          49                                                      596       10          86         4                                            597       10          42                                                      598       10          2                                                       599       10          92         0.35                                         609       10          66         2.7                                          664       10          95         1.4                                          665       10          97         1                                            666       10          83         2.1                                          667       10          89         1.6                                          676       10          32                                                      ______________________________________                                    

The compounds of the present invention can be used in the form of saltsderived from pharmaceutically or physiologically acceptable acids orbases. These salts include but are not limited to the following: saltswith inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid and, as the case may be, such organic acids asacetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium or with organic bases. Thecompounds can also be used in the form of esters, carbamates and otherconventional "pro-drug" forms, which, when administered in such form,convert to the active moiety in vivo. When the compounds are employedfor the above utility, they may be combined with one or morepharmaceutically acceptable carriers, for example, solvents, diluentsand the like, and may be administered orally in such forms as tablets,capsules, dispersible powders, granules, or suspensions containing, forexample, from about 0.05 to 5% of suspending agent, syrups containing,for example, from about 10 to 50% of sugar, and elixirs containing, forexample, from about 20 to 50% ethanol, and the like, or parenterally inthe form of sterile injectable solution or suspension containing fromabout 0.05 to 5% suspending agent in an isotonic medium. Suchpharmaceutical preparations may contain, for example, from about 0.05 upto about 90% of the active ingredient in combination with the carrier,more usually between about 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in divided doses two to fourtimes a day, or in sustained release form. For most large mammals thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparation contain a preservative to prevent thegrowth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol(e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

What is claimed is:
 1. A compound selected from those of the formula:##STR240## wherein Y is a moiety --(CH₂)--; A--B is a moiety: ##STR241##the moiety ##STR242## represents: (1) fused phenyl or fused substitutedphenyl optionally substituted by one or two substituents selected from(C₁ -C₃)lower alkyl, halogen, amino, (C₁ -C₃)lower alkoxy and (C₁-C₃)lower alkylamino; the moiety: ##STR243## is a five memberedaromatic(unsaturated) fused nitrogen containing heterocyclic ringwherein D, E and F are carbon and wherein the carbon atoms may beoptionally substituted by a substituent selected from halogen, (C₁-C₃)lower alkyl, ##STR244## and amino; q is one or two; R_(b) isindependently selected from hydrogen, --CH₃ or --C₂ H₅ ; R³ is a moietyof the formula, ##STR245## wherein Ar is a moiety: ##STR246## R⁵ isselected from hydrogen, (C₁ -C₃)lower alkyl, (C₁ -C₃)lower alkoxy andhalogen; R⁶ is a moiety of the formula: ##STR247## R_(a) is hydrogen;wherein Ar' is a moiety of the formula: ##STR248## R⁷ is selected fromhydrogen, lower alkyl(C₁ -C₃), halogen, O-lower alkyl(C₁ -C₃) and CF₃ ;R⁸ and R⁹ are independently selected from hydrogen, lower alkyl(C₁ -C₃),--S-lower alkyl(C₁ -C₃), halogen, --NH-lower alkyl(C₁ -C₃),--OCF₃, --OH,--CN, --S--CF₃, --NO₂, --NH₂, O-loweralkyl(C₁ -C₃), CF₃ and ##STR249##and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.
 2. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,3-difluorobenzamide.3. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-methoxybenzamide.4. The compound according to claim 12-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzamide.5. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,5-dichlorobenzamide.6. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide.7. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chlorobenzamide.8. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-fluorobenzamide.9. The compound according to claim 12-methyl-N-[4-[(5-oxo-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl)carbonyl]phenyl]benzamide.10. The compound according to claim 1N-[4-(3-chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)ylcarbonyl)phenyl]-2-methylbenzamide.11. The compound according to claim 1N-[4-(3-chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-methylbenzamide.12. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,3-dimethylbenzamide.13. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-ethoxybenzamide.14. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(methylthio)benzamide.15. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)ylcarbonyl)phenyl]-4-chloro-2-methoxybenzamide.16. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamide.17. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-methylphenyl]-2-methylbenzamide.18. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-methylphenyl]-2,4-dichlorobenzamide.19. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide.20. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-2-methylbenzamide.21. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-2-chloro-5-fluorobenzamide.22. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-methylphenyl]-5-fluoro-2-methylbenzamide.23. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-methylphenyl]-2-methylbenzamide.24. The compound according to claim 1N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-methylphenyl]-2-chloro-5-fluorobenzamide.25. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-chlorophenyl]-5-fluoro-2-methylbenzamide.26. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-chlorophenyl]-2-methylbenzamide.27. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-chlorophenyl]-2-chloro-4-fluorobenzamide.28. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-chlorophenyl]-2-chloro-5-fluorobenzamide.29. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-chlorophenyl]-3-fluoro-2-methylbenzamide.30. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-methylphenyl]-5-fluoro-2-methylbenzamide.31. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-methylphenyl]-2-methylbenzamide.32. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-methylphenyl]-2-chloro-4-fluorobenzamide.33. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-methylphenyl]-2-chloro-5-fluorobenzamide.34. The compound according to claim 1N-[4-[[3-[(dimethylamino)methyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-3-methylphenyl]-3-fluoro-2-methylbenzamide.35. A pharmaceutical composition useful for treating disease in a mammalcharacterized by excess renal reabsorption of water, the pharmaceuticalcomposition comprising an effective amount of a compound of claim 1, ora pharmaceutically acceptable salt, ester or prodrug form thereof, and asuitable pharmaceutical carrier.
 36. The pharmaceutical composition ofclaim 35 wherein the disease in a mammal characterized by excess renalreabsorption of water is congestive heart failure, nephrotic syndrome,hyponatremia, coronary vasospasm, cardiac ischemia, renal vasospasm,liver cirrhosis, brain edema, cerebral ischemia, or cerebralhemorrhage-stroke.
 37. A method for treating disease in a mammalcharacterized by excess renal reabsorption of water, the methodcomprising administering to a mammal in need thereof an effective amountof a compound of claim 1, or a pharmaceutically acceptable salt, esteror prodrug form thereof, and a suitable pharmaceutical carrier.
 38. Themethod of claim 37 wherein the disease in a mammal characterized byexcess renal reabsorption of water is congestive heart failure,nephrotic syndrome, hyponatremia, coronary vasospasm, cardiac ischemia,renal vasospasm, liver cirrhosis, brain edema, cerebral ischemia, orcerebral hemorrhage-stroke.